Infusion product formulation

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-... 

Most injections are formulated as aqueous solutions, with Water for Injections BP as the vehicle. The formulation of injections depends upon several factors, namely the aqueous solubility of the active ingredient, the dose to be employed, thermal stability of the solution, the route of injection and whether the product is to be prepared as a multidose one (i.e. with a dose or doses removed on different occasions) or in a singledose form (as the term suggests, only one dose is contained in the injection). Nowadays, most injections are prepared as single-dose forms and this is mandatory for certain routes, e.g. spinal injections such as the intrathecal route and large-volume intravenous infusions (section 2.2). Multidose injections may require the inclusion of a suitable... 

Specialized antibiotic formulations have been developed for DCT, with physicochemical properties chosen to confer prolonged retention in the mammary secretions (21,, ). Ziv ( ) has summarized the desirable kinetic and other properties of such a product. The following antibiotic formulations are presently approved by the U.S. Center for Veterinary Medicine, FDA for infusion into the dry mammary gland erythromycin (300 mg), oxytetracycline-HCl (426 mg), benzathine cloxacillin (500 mg), cephapirin benzathine (300 mg), novobiocin (400 penicillin (200,000 lU) novobiocin (400 mg), penicil-... 

Formidable chemical obstacles stood in the way of clinical development of these agents derived from natural products, notably in formulation of very poorly soluble compounds for intravenous infusion and in manufacture of bulk drug. For a time, production of Taxol from the bark of the Pacific Yew tree aroused public controversy, which became a story of nature and politics in pursuit of an anti-cancer drug [22]. 

Herbs from these traditions often are administered in a confusing array of preparations (Table 69.2). In the U. S. market, tablet and capsule formulations are the most popular, while overseas, teas or infusions of herbs are the most widely used. Tinctures consist of an herb steeped in a mix of alcohol and water, and extracts consist of one part herb to one part ethyl alcohol. The alcohol content can be a concern, particularly with children. Some of these products have been withdrawn by the U. S. Food and Drug Administration (FDA) for this reason but may still be available outside the United States. 

Attempts to make adhesive formulations by direct reaction of formaldehyde or its equivalent resulted in products that were excessively viscous, and the working time was too short for commercial application (57). It was concluded that formaldehyde, although readily reactive with the tannin molecule, provided much too short linkages to connect the bulky tannin molecules. This problem was circumvented by the preparation of a polymethylolphenol reagent that, when put in solution with the bark extract, formed a combination that was stable for several weeks at room temperature. When heated, the polymethylolphenol and bark extract reacted rapidly to form an infusible resin. Commercial trials were made to produce exterior-grade Douglas-fir plywood. Widespread use of the extracts for this purpose, however, was inhibited by a drop in the price of phenol below what the bark extracts could be manufactured for. (The best extract for adhesive purposes was an ammonia extract of hemlock bark converted to a sodium derivative prior to spray drying, a more costly extraction procedure than simple sodium hydroxide extraction of bark.)... 

The packaging material must not interact with the product either to adsorb substances from the product or to leach chemicals into the product. Plastics contain additives to enhance polymer performance. PVC may contain phthalate diester plasticizer, which can leach into infusion fluids from packaging. Antimicrobial preservatives such as phenylmercuric acetate are known to partition into rubbers and plastics during storage, thus reducing the formulation concentration below effective antimicrobial levels. 

Formulation studies are performed to develop a suitable vehicle to solubilize the drug for administration to patients, generally by intravenous injection or infusion in the case of cancer. The low solubility of many natural products in water poses considerable problems, but these can be overcome by use of co-solvents or emulsifying agents (surfactants) such as Cremophore EL (polyoxyethylated castor oil). 

Injectable formulations are normally administered by intravenous (IV) bolus, IV infusion, intramuscular bolus, or subcutaneous bolus, but also occasionally as subcutaneously implanted osmotically driven pumps, or as dental products via subgingival local administration. The injectable formulations are either ready-to-use solutions, concentrated solutions for dilution, or lyophilized powders that are reconstituted prior to injection. 

Small quantities of adrenaline, such as are present as an additive in local anesthetic formulations, can be dangerously potentiated by beta-adrenoceptor blockers propranolol should be discontinued at least 3 days in advance of administering such products for local anesthesia. A combined infusion of adrenaline and propranolol has been used for diagnosing insulin resistance, but it can evoke cardiac dysrhythmias, even in patients without signs of coronary disease (17). 

Vancomycin is a narrow-spectrum glycopeptide antibiotic with potent antistaphylococcal activity. It was developed in the early 1950s. Early formulations contained substantial impurities, which were presumably responsible for some adverse reactions (1). When rapid infusion rates are avoided, vancomycin is rarely associated with serious toxicity. Reviews have suggested that the potential for vancomycin to cause significant ototoxicity or nephrotoxicity has been exaggerated (2,3). Improved manufacturing has resulted in a purer product and fewer toxic effects, but vancomycin is still associated with potentially serious adverse reactions (4). 

In several cases the special nature of a formulation will preclude dilution by an aqueous infusion fluid. Injectable products containing phenytoin, digoxin and diazepam may come into this category if they are formulated in a nonaqueous but water-miscible solvent (such as an alcohol-water mixture) or as a solubilised (e.g. micellar) preparation. Addition of the formulation to water may result in precipitation of the dmg, depending on the final concentration of the dmg and solvent. It has been suggested that precipitation of the relatively insoluble diazepam may account for the high (3.5%) incidence of thrombophlebitis which occurs when diazepam is given intravenously. 

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