Parenteral preparations preservation

Some compounded preparations are naturally preserved, as in the case of certain syrups and elixirs others require the addition of a preservative. Preservatives are commonly added to products to minimize microbial growth, as in the case of oral liquids, topicals, and multi-dose parenterals. A preservative is selected based upon its characteristics, including concentration, pH, taste, odor, and solubility. 

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-... 

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... 

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. 

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. 

Preservatives are added to various dosage forms and cosmetic preparations to prevent microbial contamination. In parenteral and ophthalmic preparations, preservatives arc used to maintain. sterility in the event of accidental contamination during use. An ideal prc.scrvative would be effective at low concentrations against all possible microorganisms, be nontoxic and compatible with other constituents of the preparation, and be stable for the. shelf life of the preparation. The ideal pre.servative dues not exi.st. but there is quite a bit of experience with some of them. In srnne ca.ses. combinations of preservative agents arc used to approximate a mixture of ideal features. 

D. Sulfite preservative in some parenteral preparations may cause hypersensitivity reactions. 

Of chlorocresol (see Fig. 23.18), p-chloro-m-cresol and metacresol (m-cresol, see Fig. 23.19) only the last one is mentioned as a preservative in parenteral preparations (see Sect. 13.5.9). Chlorocresol is used as a disinfectant of clean rooms (see Table 31.5). The solubility of chlorocresol in water is 0.4 % the active concentration is 0.1 %. The solubility of metacresol is approximately 2 %. Solutions of chlorcresol or metacresol resist autoclaving. 

Phenol is up to 7 % soluble in water. The active concentration is 0.5 %. It is used as a preservative in parenteral preparations and exceptionally in cutaneous preparations, because of the unpleasant smell. 

In contrast, parenteral suspensions have relatively low solids contents, usually between 0.5 and 5%, with the exception of insoluble forms of penicillin in which concentrations of the antibiotic may exceed 30%. These sterile preparations are designed for intramuscular, intradermal, intralesional, intraarticular, or subcutaneous injection. Syringeability is an important factor to be taken into consideration with injectable dosage forms. The viscosity of a parenteral suspension should be sufficiently low to facilitate injection. Common suspending vehicles include preserved isotonic saline solution or a parenterally acceptable vegetable oil. Ophthalmic and optic suspensions that are instilled into the eye/ear must also be prepared in a sterile manner. The vehicles are essentially isotonic and aqueous in composition. The reader should refer to Chapter 12 for further discussion on parenteral products. 

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. 

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. 

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. 

Phenylmercuric salts are used as antimicrobial preservatives mainly in ophthalmic preparations, but are also used in cosmetics see Section 16), parenteral, and topical pharmaceutical formulations see Table I. 

Sodium metabisulfite is used as an antioxidant in oral, parenteral, and topical pharmaceutical formulations, at concentrations of 0.01-1.0% w/v. Primarily, sodium metabisulfite is used in acidic preparations for alkaline preparations, sodium sulfite is usually preferred see Section 18. Sodium metabisulfite also has some antimicrobial activity, which is greatest at acid pH, and may be used as a preservative in oral preparations such as syrups. 

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. 

Included in the FDA Inactive Ingredients Guide (IM, IV, and SC injections ophthalmic, otic, and topical preparations). Included in nonparenteral and parenteral medicines licensed in the UK. In the UK, the use of thimerosal in cosmetics is limited to 0.003% w/w (calculated as mercury) as a preservative in shampoos and hair-creams, which contain nonionic emulsifiers that would render other preservatives ineffective. The total permitted concentration (calculated as mercury) when mixed with other mercury compounds is 0.007% w/w. Included in the Canadian List of Acceptable Non-medicinal Ingredients. 

Sterile aqueous solutions prepared with high purity ascorbic acid and pyrogen-free distilled water in glass-lined equipment under absolute sanitary operations and filled into ampules are necessary for injectable solutions for parenteral use in humans and animals. For all injectable products, it is important to select container, stopper, preservative, and other ingredients that are compatible. 

A. Parenteral. Propofol (Diprivan) 1% (10 mg/mL) emulsion in 10% soybean oil with 2.25% glycerol and 1.25% purified egg phospholipid in 20-, 50-, or 100-mL vials and a 50-mL prefilled syringe. Contains disodium EDTA or sodium metabisulfite in the US formulation as preservatives. A 2% (20 mg/mL) emulsion has been formulated to provide the same amount of drug with less lipid concentration, but is not yet approved in the United States. Note Propofol is provided as a ready-to-use preparation, but if dilution is necessary, only use D5W and don t dilute to conoentrations less than 2 mg/mL. 

Another possible explanation of the observed reactions are the additives in pharmaceutical preparations. Thus Lagerholm et al. (1958) reported a case of hypersensitivity to benzyl alcohol added as a preservative to vitamin B 2 preparations, resulting in urticaria after injection, Hovding (1968), however, was not able to demonstrate a positive skin reaction either with benzyl alcohol or with cobalt chloride. However, skin tests with commercial brands of cyanocobalamin and hydroxocobalamin as well as with purified cyanocabalamin and hydroxocobalamin were positive. Malten (1975) reports a flare reaction in a woman due to the third injection of 250 pg vitamin B12. Prick and patch tests, however, remained negative. A recent short review of reactions after administration of vitamin Bj2 preparations was published by Meuwissen (1978). An extensive review covering the literature up to 1975 was presented by Faivre et al. (1975). The authors conclude that, despite the widespread use of vitamin B12 preparations, cases of accidents after vitamin Bi2 administration are very rare, but nevertheless are a potential risk. Therefore, skin and immunologic tests should be made prior to administration and especially parenteral application of the vitamin. The authors do not make an explicit statement as to a definite allergic mechanism of the observed phenomena. 

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