Excipients parenteral formulations

BMS-204352, a novel substituted 3-fluorooxindole, is a potassium channel opener being developed for the treatment of stroke. Nassar et al. [96] reported on the development of a non-aqueous parenteral formulation of BMS-204352. This formulation was composed of a mixture of PEG 300, polysorbate 80, ethanol and water. The authors reported on the formation of 1-hydroxymethyl adduct of BMS-204352 (formaldehyde adduct), which was linked with residual levels of formaldehyde in the polymeric excipients. 

Akers MJ. Excipient-drug interactions in parenteral formulations. J Pharm Sci 2002 91 2283-2300. 

Higher concentrations of a chemical entity may cause a pharmacological response whereas lower concentrations are incapable of doing so. For example, edetate calcium disodium (9) at a formulated concentration of 20% is indicated as a drug for the treatment of lead poisoning and lead encephalopathy while it can be found commonly present as an excipient in concentrations ranging from 0.01% to 0.1% in parenteral formulations to prevent oxidation of the active ingredient. 

The parenteral route of administration is associated with several major disadvantages (see Section 3.5.2). Parenteral administration is invasive and may require the intervention of trained medical professionals. Strict regulations for parenteral formulations govern their use and generally dictate that they are as simple as possible and the inclusion of excipients in the formulation is kept to an absolute minimum. Furthermore, developing a DDTS requires an enormous amount of R D investment in terms of cost, effort and time,... 

Buffers can also be provided in parenteral formulations to ensure the required pH needed for solubility and/or stability considerations. Other excipients included in parenteral products are preservatives (e.g., benzyl alcohol, p-hydroxybenzoate esters, and phenol), antioxidants (e.g., ascorbic acid, sodium bisulfite, sodium metabisulfite, cysteine, and butyl hydroxy anisole), surfactants (e.g., polyoxyethylene sorbitan monooleate), and emulsifying agents (e.g., polysorbates). An inert gas (such as nitrogen) can also be used to enhance drug stability. Stability and solubility can also be enhanced by the addition of complexation and chelating agents such as the ethylenediaminetetraacetic acid salts. For a more detailed list of approved excipients in parenteral products, the reader should consult the monographs within the USP. 

Several new excipients are being evaluated in order to increase the solubility or improve the stability of parenteral drugs. Cyclodextrins have been tried for the above reasons. Currently, there are two FDA approved parenteral products that have utilized a and y-cyclodextrins. p-cyclodextrin is unsuitable for parenteral administration because it causes necrosis of the proximal kidney tubules upon IV and subcutaneous administration. Hydroxypropyl p-cyclodextrin (HPpCD) and sulfobutylether p-cyclodextrin (SBE-7-p-CD) have shown the most promise. Captisol is the trade name of SBE-7-p-CD and is anionic. Currently, two CaptisoF based small molecule IV and IM drug formulations are in Phase III clinical trials in the United States. One parenteral formulation that utilizes HPpCD (Cavitron ) is in Phase II/III clinical trials, and another (Sporanox) has been approved by... 

Albumin occurs naturally in the body, comprising about 60% of all the plasma proteins. As an excipient, albumin is used primarily in parenteral formulations and is generally regarded as an essentially nontoxic and nonirritant material. Adverse reactions to albumin infusion rarely occur but include nausea, vomiting, increased salivation, chills, and febrile reactions. Urticaria and skin rash have been reported. Allergic reactions. 

Dimethylacetamide is used in pharmaceutical preparations as a solvent in parenteral formulations and is generally regarded as a nontoxic material when used as an excipient. Animal toxicity studies indicate that dimethylacetamide is readily absorbed into the bloodstream following inhalation or topical application. Repeated exposure to dimethylacetamide may be harmful and... 

Powell ME, Nguyen T, and Baloian L. Compendium of Excipients for Parenteral Formulations, yParewt Technol 1998 52 238-411. 

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