Excipients for Injectable Formulations

VePeSid Etoposide 30% ethanol, 60% PEG 300, 8% Tween 80, 2% benzyl alcohol IV infusion 

Faslodex Fulvestrant Ethanol, benzyl alcohol, benzyl benzoate, castor oil IM 

Prograf Tacrolimus 20% Cremophor RH60, 80% ethanol IV infusion 

Viadur Leuprolide acetate DMSO SC, sustained release 

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Naturally this is not a standard rule, because other excipients and the drug itself may also play a role in the phenomenon. Some of the buffers commonly used for injectable formulations are listed in Table 6. 

Parenteral is defined as situated or occurring outside the intestine, and especially introduced otherwise than by way of the intestines —pertaining to essentially any administration route other than enteral. This field is obviously too broad for an adequate focus in one book, let alone one chapter. Many have nonetheless used the term synonymously with injectable drug delivery. We restrict ourselves to this latter usage. This would thus include intravenous, intramuscular, subcutaneous, intrathecal, and subdural injection. In this chapter we discuss the theoretical and practical aspects of solubilizing small molecules for injectable formulation development and will examine the role of surfactants and other excipients in more recent parenteral delivery systems such as liposomes, solid-drug nanoparticles and particulate carriers. 

Formulation Aranesp is formulated as a sterile, colorless, preservative-free protein solution for intravenous (IV) or subcutaneous (SC) administration. There are two formulations the polysorbate solution includes excipients such as polysorbate 80, sodium phosphate monobasic monohydrate, sodium phosphate dibasic anhydrous, and sodium chloride in water-for-injection while the albumin solution contains albumin, sodium phosphate monobasic monohydrate, sodium phosphate dibasic anhydrous, and sodium chloride in water-for-injection. The pH for both formulations is 6.2 + 0.2. 

Excipients used in injectable formulations have to meet several stringent requirements. A positive identification test uniquely applicable to the excipients is required (e.g., infrared spectrophotometry and chromatography). It is important that manufacturers identify and set appropriate limits for impurities. These limits should be based upon appropriate toxicological data, or the limits described in national compendial requirements. Manufacturing processes should be adequately controlled so that the impurities do not exceed such established specifications. Solvents or catalysts used in the excipient production process should be removed to appropriate levels. If naturally derived, excipients should meet endotoxin levels and may require further testing for bovine spongiform encephalopathy (BSE) /... 

To work around this concentration limitation, formulation scientists often use a solid-state formulation as a means to achieving a higher protein concentration for the final drug product. By reconstituting the solid formulation with less water than was used to initially formulate the drug, one gets an increased protein concentration in the reconstituted product, as depicted in Fig. 1. It is important for the formulation scientist to remember that, in addition to the protein, the excipients in the formulation are also increased in concentration when the solid formulation is reconstituted to a lower final volume. Care should be taken to maintain a suitable final product osmolality for injection. 

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. 

Bacteriostatic Water for injection (USP), used to dilute or reconstitute medications for intravenous use. The content of benzyl alcohol in a lot of injectable pharmaceutical formulations needs to be considered carefully. The view still taken in many countries that the additives and excipients in medicines are trade secrets must be deplored. The duty to declare them is only realized in some countries. 

Peanut oil is used as an excipient in pharmaceutical formulations primarily as a solvent for sustained-release intramuscular injections. It is also used as a vehicle for topical preparations and as a solvent for vitamins and hormones. In addition, it has been part of sustained-release bead formulations, nasal drug delivery systems, and controlled-release injectables. ... 

Parenteral administration is the primary route of testing delivery for nucleic acid therapeutics irrespective of whether systemic or local effects are desired. However, to some extent, pulmonary and oral routes are also investigated as potential routes for local targeting to treat cystic fibrosis or colonic tissue (171-173). For nonparenteral delivery, the use of pharmaceutical excipients in the formulation is critical. In addition, the production costs of nucleic acid therapeutic-containing drug delivery systems should be minimized. Even for intravenously or subcutaneously injected nucleic acid-based therapeutics, the use of protective carriers is most likely necessary, and advantageous as compared to injection of the naked RNA or DNA. Carriers can be divided into viral or... 

Two formulations contain excipients as follows polysorbate solution contains 0.05 mg of polysorbate 80, 2.12 mg of sodium phosphate monobasic monohydrate, 0.66 mg of sodium phosphate dibasic anhydrous, and 8.18 mg of sodium chloride in water for injection, LISP (per 1 mL) at pH 6.2 + 0.2. Albumin solution contains 2.5 mg of albumin (human), 2.23 mg of sodium phosphate monobasic monohydrate, 0.53 mg of sodium phosphate dibasic anhydrous, and 8.18 mg of sodium chloride in water for injection, LISP (per 1 mL) at pH 6.0 + 0.3. 

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). 

Other additives such as antimicrobial agents, antioxidants, buffers and tonicity-adjusting agents can be included in injection formulations and it is the responsibility of the pharmacist to check that all excipients and adjuvants are suitable (benzyl alcohol, ethanol, sulfites, sodium content, etc.). Nevertheless, one is left with a difficult choice over excipients, either those for which toxicity is known and therefore predictable, or those with safety profiles that have not been established in children (see under Critical excipients, page 55). The pH and osmo-larity of the preparation must also be checked before administration by another route. 

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