Preservatives parenteral formulations

Preservatives are necessary when developing multidose parenteral formulations that involve more than one extraction from the same container. Their primary function is to inhibit microbial growth and ensure product sterility throughout the shelf life or duration of use of the drug product. Commonly used preservatives include benzyl alcohol, phenol, and m-cresol. Although preservatives have a long history of use with small-molecule parenterals, the development of protein formulations that include... 

Buffers can also be provided in parenteral formulations to ensure the required pH needed for solubility and/or stability considerations. Other excipients included in parenteral products are preservatives (e.g., benzyl alcohol, p-hydroxybenzoate esters, and phenol), antioxidants (e.g., ascorbic acid, sodium bisulfite, sodium metabisulfite, cysteine, and butyl hydroxy anisole), surfactants (e.g., polyoxyethylene sorbitan monooleate), and emulsifying agents (e.g., polysorbates). An inert gas (such as nitrogen) can also be used to enhance drug stability. Stability and solubility can also be enhanced by the addition of complexation and chelating agents such as the ethylenediaminetetraacetic acid salts. For a more detailed list of approved excipients in parenteral products, the reader should consult the monographs within the USP. 

Benzyl alcohol is the most common antimicrobial preservative present in parenteral formulations (Table 5). This observation is consistent with other surveys. ° Parabens are the second most common preservatives. Surprisingly, thimerosal is also common, especially in vaccines, even though some individuals are sensitive to mercuries. Several preservatives can volatilize easily (such as benzyl alcohol, and phenol) and, therefore, should not be used for lyophilized dosage form. Chlorocresol is purported to be a good preservative... 

Sodium sulfite is used as an antioxidant in applications similar to those for sodium metabisulfite It is also an effective antimicrobial preservative, particularly against fungi at low pH (0.1% w/v of sodium sulfite is used). Sodium sulfite is used in cosmetics, food products, and pharmaceutical applications such as parenteral formulations, inhalations, oral formulations, and topical preparations. 

Preservatives should not usually be included in parenteral formulations except where a multidose product is being developed. The Committee for Proprietary Medicinal Products (CPMP) Notes for Guidance on Inclusion of Antioxidants and Antimicrobial Preservatives in Medicinal Products states that the physical and chemical compatibility of the preservative (or antioxidant) with the other constituents of the formulation, the container and closure must be demonstrated during the development process. The minimum concentration of preservative should be used, which gives the required level of efficacy, as tested using pharmacopoeial methods. Certain preservatives should be avoided under certain circumstances, and preservatives should be avoided entirely for some specialised routes. The guidelines also require that both the concentration and efficacy of the preservative are monitored over the shelf life of the product. In multidose injectable products, the efficacy of the preservative must be established under simulated in-use conditions. Table 9.2 shows some of the most commonly encountered preservatives in licensed products and their typical concentrations. 

D. Parenteral formulations that contain sulfite preservatives may precipitate bronchospasm in susceptible individuals. 

Substances that have been used as preservatives for disperse systems include chlorocresol, chlorobutanol, benzoates, phenylmercuric nitrate, parabens, and others [76,77]. The use of cationic antimicrobial agents such as quaternary ammonium compounds (e.g., benzalkonium chloride) is contraindicated in many cases because they may be inactivated by other formulation components and/or they may alter the charge of the dispersed phase. Clay suspensions and gels should be adequately preserved with nonionic antimicrobial preservatives. The use of preservatives is generally limited to products that are not intended for parenteral use. Intravenous injectable... 

Another important component of most vaccine formulations is a suitable preservative. The three most commonly used preservatives in available vaccines are phenol, 2-phenoxyethanol, and ethyl mercurithiosalicylate (thimerosal). Thimerosal, in particular, is used in multidose vials as an antimicrobial preservative. Concerns about the presence of mercury in thimerosal (25 pg/dose) has led to FDA stopping the use of this preservative in all vaccines by an amendment to the FDA Modernization Act of 1997. By 2001, thimerosal was removed from most childhood vaccines as a precautionary measure. The sources of all of the preservatives for vaccines are the same suppliers that supply preservatives for the parenteral dosage forms (J. T. Baker, Aldrich, Spectrum, etc. from U.S.A.). Table 2 lists some of the preservative concentrations in common vaccines. 

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... 

Preservatives In addition to those processing controls mentioned above (Section 3.1.4.3), the sterility of a product may be maintained through the addition of antimicrobial preservatives. Preservation against microbial growth is an important aspect of multidose parenteral preparations as well as other formulations that require preservatives to minimize the risk of patient infection upon administration, such as infusion products [52], Aqueous liquid products are prone to microbial contamination because water in combination with excipients derived from natural sources (e.g., polypeptides, carbohydrates) and proteinaceous active ingredients may serve as excellent media for the growth [57], The major criteria for the selection of an appropriate preservative include efficiency against a wide spectrum of micro-... 

Multivitamin products for parenteral administration are available in a variety of compositions from different manufacturers. As different formulations are available generally, valid stability information cannot be provided. Stability data obtained on vitamins, derived from studies of a single vitamin, cannot be accurately extrapolated to all multivitamin preparations because of possible vitamin, preservative, and excipient interactions. 

The need for a multidose formulation may also dictate the use of a solid-state formulation. As the name implies, multidose products are intended to provide the patient with a product that contains several doses of the therapeutic within one container. Multidose formulations contain preservatives to kill any bacteria and prevent mold growth that may result from repeated entry into the drug product. Phenol and benzyl alcohol are two widely used preservatives in protein-based parenteral pharmaceuticals. Frequently, the addition of a preservative to the formulation compromises the long-term stability of the drug product, typically because the protein becomes physically unstable and/or exhibits oxidation. If the formulation scientist can obtain sufficient short-term stability (e.g., 2 weeks) for a formulation containing a preservative, then the use of a solid-state product may enable production of a multiuse formulation. In this case, the preservative is NOT added to the liquid bulk used to prepare the solid state. Instead, when the solid-state formulation is reconstituted prior to use, a preservative is included in the water for reconstitution. Thus the final product to be used is a multidose formulation that will experience only short-term exposure to the preservative. 

Solution formulations, however, do not typically have these same constraints, and complexation provides an alternative to the use of non-aqueous solvents or large volumes. A few derivatized CDs (e.g., hydro-xypropyl and sulfobutyl ether) can be safely administered by parenteral routes. This is often where complexation and its improvements in aqueous solubility can be most readily utilized. The derivatized CDs often can be used to replace cosolvents such as ethanol, polyethylene glycol, and lipids, as well as provide an alternative to the use of emulsions and liposomes. The hydroxypropyl and sulfobutyl ether derivatives are stable in solution and can be readily autoclaved, often improving the heat stability of drugs. There are however, reports of complexation of CDs with anti-oxidants and preservatives " with both decreased and increased efficacy. ... 

Emulsions are formulated for virtually all the major routes of administration, and there are a number of dermatological, oral and, parenteral preparations available commercially. The internal phase may contain water-soluble drugs, preservatives, and flavoring agents whilst the oil phase may itself be therapeutically active or may act as a carrier for an oil-soluble drug. Such preparations provide an effective approach to... 

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. ... 

Benzyl alcohol is an antimicrobial preservative used in cosmetics, foods, and a wide range of pharmaceutical formulations, including oral and parenteral preparations, at concentrations up to 2.0% v/v. In cosmetics, concentrations up to 3.0% v/v may be used as a preservative. Concentrations of 5% v/v or more are employed as a solubilizer, while a 10% v/v solution is used as a disinfectant. 

Chlorobutanol is primarily used in ophthalmic or parenteral dosage forms as an antimicrobial preservative at concentrations up to 0.5% w/v see Section 10. It is commonly used as an antibacterial agent for epinephrine solutions, posterior pituitary extract solutions, and ophthalmic preparations intended for the treatment of miosis. It is especially useful as an antibacterial agent in nonaqueous formulations. Chlorobutanol is also used as a preservative in cosmetics [see Section 16) as a plasticizer for cellulose esters and ethers and has been used therapeutically as a mild sedative and local analgesic. 

Chlorocresol is used primarily as a preservative in topical pharmaceutical formulations but has also been used in nebulized solutions and ophthalmic and parenteral preparations. It should not, however, be used in formulations for intrathecal, intracisternal, or peridural injection. 

Methylparaben (0.18%) together with propylparaben (0.02%) has been used for the preservation of various parenteral pharmaceutical formulations see Section 14. 

Phenol is used mainly as an antimicrobial preservative in parenteral pharmaceutical products. It has also been used in topical pharmaceutical formulations and cosmetics see Table I. 

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