Excipients, injectable products

The incorporation of certain excipients in products is deemed to be undesirable. Examples are the inclusion of mercurial preservatives, the inclusion of benzyl alcohol in parenteral products for use in children, the use of benzoic acid esters in injections, and the inclusion of sulfites and metabisulfites in products in general. If it is intended to use any of these materials, then a full justification will be required. 

Nema S, Washkuhn RJ, Brendel RJ. Excipients and their use in injectable products. PDA J Pharm Sci Tech 1997 51 166-170. 

As discussed above, cosolvents can be an effective way to alter the solubility and stability of compounds. In formulating a parenteral product, often these two parameters can be exploited to produce a commercially acceptable, elegant product. Often cosolvents can be used to concentrate a formulation to allow production of a dosage form for presentation as an ampule or vial. The concentrated ampule or vial is then diluted before administration to the patient. Nema et al. [107] has reviewed excipient use, including cosolvents, in commercially available injectable products. 

This chapter is a comprehensive review of the excipients included in the injectable products marketed in the United States, Europe, and Japan. A review of the literature indicates that only a few articles that specifically deal with the selection of parenteral excipients have been published. However, excipients included in other sterile dosage forms not administered paren-terally, such as solutions for irrigation, ophthalmic or otic drops, and ointments, will not be covered. 

Simply because an excipient is listed as Generally Recognized As Safe (GRAS) does not mean that it can be used in parenteral dosage form. The GRAS list may include materials that have been proven safe for food (oral administration) but have not been deemed safe for use in an injectable product. This makes it difficult for the formulation development scientist to choose additives during the dosage form development. 

The excipient manufacturer must document the sanitizing of critical processing equipment such as centrifuges and dryers. Any manipulation of sterile excipients post-sterilization must be performed as a validated aseptic process. This is particularly important for those excipients which are not further sterilized prior to packaging into final containers. In some instances, the compendial monographs may specify that an excipient which does not meet parenteral grade standards be labelled as not suitable for use in the preparation of injectable products. Ethylene oxide is sometimes used for the sterilization of powders. The manufacture should validate that the ethylene oxide exposure does, in fact, produce a sterile product. 

Intravenous aqueous injections provide an excellent means of achieving a rapid therapeutic response. Parenteral product design, eg, vehicle and other excipient selection, as well as choice of route of adrninistration, can prolong therapeutic activity and increase onset times. Thus, oily solutions, suspensions, or emulsions can be adrninistered by subcutaneous or intramuscular routes to create prolonged effect, ie, depot injection (28). 

Technetium-99m teboroxime is a myocardial imaging agent and is excreted primarily by the hepatobiliary system. It is rapidly taken up by the myocardium and mosdy washes out within 30 minutes. Imaging protocols are performed immediately after injection. The product is a lyopbili ed mixture of boronic acid, dioxine, and other excipients, and the agent is formed with a beating step. 

Many drugs, including many biopharmaceuticals, are administered to localized areas within the body by, for example, s.c. or i.m. injection. Local toxicity tests appraise whether there is any associated toxicity at/surrounding the site of injection. Predictably, these are generally carried out by s.c. or i.m. injection of product to test animals, followed by observation of the site of injection. The exact cause of any adverse response noted (i.e. active ingredient or excipient) is usually determined by their separate subsequent administration. 

The product is presented in lyophilized format and contains sodium phosphate, sucrose and polysorbate as excipients. It is usually administered as once-weekly s.c. injections, typically for periods of 6 months. 

The purified product is presented as a solution and contains sodium citrate, EDTA, sodium chloride and polysorbate 80 as excipients. A daily (s.c.) injection of 100 mg is recommended for patients with rheumatoid arthritis. This inflammatory condition is (not surprisingly) characterized by the presence of high levels of IL-1 in the synovial fluid of affected joints. In addition to its pro-inflammatory properties, IL-1 also mediates additional negative influences on the joint/bone, including promoting cartilage degradation and stimulation of bone resorption. 

Neumega is the tradename given to the IL-ll-based product approved for the prevention of thrombocytopenia. The product is produced in engineered E. coli cells and is presented as a purified product in freeze-dried format. Excipients include phosphate buffer salts and glycine. It is reconstituted (with water for injections) to a concentration of 5 mg ml-1 before s.c. administration. 

Enbrel is a product now approved for medical use that is based upon this strategy. The product is an engineered hybrid protein consisting of the extracellular domain of the TNF p75 receptor fused directly to the Fc (constant) region of human IgG (see Box 13.2 for a discussion of antibody structure) The product is expressed in a CHO cell line from which it is excreted as a dimeric soluble protein of approximately 150 kDa. After purification and excipient addition (mannitol, sucrose and trometamol), the product is freeze-dried. It is indicated for the treatment of rheumatoid arthritis and is usually administered as a twice-weekly s.c. injection of 25 mg product reconstituted in WFI. Enbrel functions as a competitive inhibitor of TNF, a major pro-inflammatory cytokine. Binding of TNF to Enbrel prevents it from binding to its true cell surface receptors. The antibody Fc component of the hybrid protein confers an extended serum half-life on the product, increasing it by fivefold relative to the soluble TNF receptor portion alone. 

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