Parenteral preparations formulation

Irritation. Tissue irritation upon injection, and the accompanying damage and pain, is a concern that must be addressed for the final formulation, which is to be either tested in humans or marketed, rather than for the active ingredient. This is because most irritation factors are either due to or influenced by aspects of formulation design (see Avis, 1985, for more information or parenteral preparations). These factors are not independent of the route (TV, IM, or SC) that will be used and, in fact (as discussed later), are part of the basis for selecting between the various routes. 

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-... 

The use of cosolvents in small-volume parenteral preparations is often critical due to the limited volume of solution that can be administered by a single injection. Thus, the required dose of drug must often be incorporated in 1 or 2mL of solution. Table 6 lists parenteral products containing cosolvents. The cosolvents most often used include ethanol, propylene glycol, glycerin, PEG 400, and, sometimes, dimethylacetamide. Other cosolvents, such as DMSO, have been used as solvents for parenteral formulations of experimental anticancer agents however, their use is restricted due to toxicity and potential incompatibilities with plastic administration devices. ... 

Vineland, NJ) or over-the-counter cosmetic creams promoted for improved hydration (L Oreal, Paris and Dior, Paris). More recently, parenteral liposome formulations of amphotericin B, doxorubicin, and dau-norubicin have been approved and marketed (ABELCET, Elan, the Liposome Co., Inc, Princeton, NJ AmBisome and DaunoXome, Nexstar/Fujisawa, Deerfield Park, IL Amphotec and Doxil, Sequus/ Alza, Menlo Park, CA), with others on the horizon for applications in photodynamic therapy. Although the vast majority of liposome preparations are constructed from phospholipids, other nonphospholipid materials can be used either alone or in mixtures to form bilayer arrays. One such example is Amphotec, which utilizes sodium cholesteryl sulfate as the primary lipid. Other liposome forming materials may include but are not limited to fatty-acid compositions, ionized fatty acids, or fatty acyl amino acids, longchain fatty alcohols plus surfactants, ionized lysophospholipids or combinations, non-ionic or ionic surfactants and amphiphiles, alkyl maltosides, a-tocopherol esters, cholesterol esters, polyoxyethylene alkyl ethers, sorbitan alkyl esters, and polymerized phospholipid compositions. ° ... 

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... 

Buffers are added to a formulation to adjust the pH in order to optimize solubility and stability. For parenteral preparations, the pH of the product should... 

Albumin is primarily used as an excipient in parenteral pharmaceutical formulations, where it is used as a stabilizing agent for formulations containing proteins and enzymes. Albumin has also been used to prepare microspheres and microcapsules for experimental drug-delivery systems. ... 

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. 

The use of dimethyl sulfoxide to improve transdermal delivery has been reported for ciclosporin, timolol, and a wide range of other drugs.Dimethyl sulfoxide has also been used in the formulation of an injection containing allopur-inol. It has also been investigated for use in an experimental parenteral preparation for the treatment of liver tumors. ... 

Ethyl oleate is primarily used as a vehicle in certain parenteral preparations intended for intramuscular administration. It has also been used as a solvent for drugs formulated as biodegradable capsules for subdermal implantation and in the preparation of microemulsions containing cyclosporin. ... 

Glycerin is used in a wide variety of pharmaceutical formulations including oral, otic, ophthalmic, topical, and parenteral preparations see Table I. 

Monothioglycerol is used as an antioxidant in pharmaceutical formulations, mainly in parenteral preparations. Monothioglycerol is reported to have some antimicrobial activity. It is also widely used in cosmetic formulations such as depilating agents. 

Activity may be improved by using combinations of parabens, as additive effects occur. Propylparaben has been used with methylparaben in parenteral preparations, and is used in combination with other parabens in topical and oral formulations. Activity has also been reported to he improved by the addition of other excipients see Methylparaben. 

Repeated injections cause significant local trauma and injections cannot be continued indefinitely. Some drug formulations are not suitable for subconjunctival injection (e.g. parenteral preparations of NSAIDs). 

Distilled water is often used in the formulation of oral and topical pharmaceutical preparations and a low bacterial count is desirable. It is also used after distillation with a specially designed still, often made of glass, for the manufacture of parenteral preparations and a post-distillation heat sterilization stage is commonly included in the process. Water for such preparations is often stored at 80°C to prevent bacterial growth and the production of pyrogenic substances which accompany such growth. 

Drug absorption from an intramuscular injection site is mainly determined by the formulation of the parenteral preparation and is influenced by the... 

The extent of absorption (systemic availability) of a drug is estimated by the method of corresponding areas. Comparison of total AUC following the intramuscular injection of a parenteral preparation (solution or suspension) with that following the intravenous injection of a bolus dose of the drug (parenteral solution) provides an estimation of absolute bioavailability, while comparison of AUCs following intramuscular injection of different parenteral preparations (one of which must be a reference formulation) at the same injection site or of the same parenteral preparation at different injection sites estimates the relative bioavailability. A crossover design with an appropriate washout period between the phases of the bioavailability study should be used whenever feasible. 

Since the administration routes are mainly parenteral, the formulation has to be injectable. An injectable formulation requires specific excipients, ways of preparation and formulation types liquid, suspension, or solid formulations. In the development of protein drugs, various formulation principles are used. In Table 5, examples of some of the formulation principles are given. 

Photochemical reactivity of drug formulations is an important aspect to consider during development, production, storage, and use of pharmaceutical preparations. However, photochemical stability of drug substances is rarely as well documented as thermal stability of the compounds. For instance, in order to obtain a high sterility assurance level of the product, a parenteral preparation is sterilized in its final container if possible. Steam sterilization at minimum temperature of 121°C for... 

In busy hospital wards, the nursing staff often removes the outer cartons from parenteral products, and the preparations are stored without any protection against optical irradiation. In addition, ex tempore preparations are produced in the hospital pharmacy without outer protection and not usually protected when distributed to the wards (e.g., by use of aluminum foil) unless specifically instructed. According to the European Pharmacopoeia (2002), containers for parenteral preparations are to be made when possible from materials (usually glass or plastic materials) that are sufficiently transparent to permit visual inspection of the contents. As a consequence, the containers will offer no protection, or in some cases only limited protection, against photochemical decomposition of the drug substance or the formulation. 

As a consequence, knowledge of photochemical stability and possible photochemical stability problems is of great importance in regard to parenteral preparations, especially infusions (see Table 14.1). Few systematic studies have been performed. Several factors can influence photochemical stability of dilute solutions and disperse systems, which constitute the main part of parenteral formulations. This chapter is focused on the different parameters that, theoretically, may influence photochemical stability of parenterals. Of course, the best way to stabilize the preparations is by preventing exposure to optical irradiation, an option not often accomplished in practice. Thus, it is valuable to know the factors that can influence photochemical stability of the products, as well as to prepare protocols for the management of parenterals at each hospital ward based on this knowledge. 

Aqueous parenteral preparations can contain trace amounts of heavy metal ions in concentrations sufficient to catalyze oxidative reactions. Aqueous parenterals are produced with the use of Water for injection, which complies with the limit test for heavy metals (European Pharmacopoeia, 2002). This is, however, no guarantee for exclusion of metal ions. Heavy metal contamination brought into the formulation by excipients is also a problem, especially for sugars, phosphate, and citrate (Nema et al., 2002). Heavy metals may also be extracted from the container by the preparation (European Pharmacopoeia, 2002 see Section 14.3). Moreover, trace elements like zinc, copper, manganese, and chromium constitute important components in several parenteral nutrition formulas (Trissel, 2001). 

Parenteral preparations are regularly prepared aseptically a short time or immediately prior to administration. Compounds susceptible to hydrolysis or oxidative decomposition in solution are preferentially stored as dry powders, concentrates under an inert atmosphere, or in combination with stabilizers. Concentrates for injections or infusions (European Pharmacopoeia, 2002) are diluted prior to administration, usually with sterilized Water for injection (European Pharmacopoeia, 2002) or sterile, isotonic solutions of sodium chloride, glucose, dextran, or buffer (see Table 14.3). Powders for injections or infusions (European Pharmacopoeia, 2002) are dissolved or suspended in the same media. Vitamins are aseptically added ex tempore to TPN preparations due to poor stability and the risk of precipitation (Hutchinson, 1998), as are trace metals that may influence the stability of the TPN formulation. A limited number of drugs may also be dissolved in the TPN infusion prior to administration (Hutchinson, 1998). 

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