Excipients in parenteral formulations: selection considerations and effective utilization with small molecules and biologics

Abstract

Excipients form a major component of pharmaceutical formulations and are classified as any ingredient other than the active ingredient which is included within the product formulation to improve drug product performance. Functional uses of excipients include improving solubility and stability, safety and efficacy, as bulking agents in lyophilized formulations, tonicity agents, and aiding in controlled or prolonged drug delivery. Parenteral formulations are sterile, pyrogen-free; free of particulate matter and by-pass the body's natural defense mechanisms. Excipients may demonstrate a synergistic effect when combined with an active ingredient but may also lead to unwanted reactions with the drugs and packaging components. Ideal excipients are required to be considered safe, inert and multifunctional. Contrary to the past, safety of excipients needs to be well established in order for their use in the pharmaceutical formulations. Therefore, careful consideration should be given while selecting an excipient. This review article provides an overview of the excipients used exclusively in small molecule and biological parenteral products including solutions, suspensions, and lyophilized formulations, information on the possible drug-excipient and drug-packaging interactions and the regulatory requirements for the use of pharmaceutical excipients. The readers will be able to have a comprehensive understanding of the excipients used in parenteral formulations.

A spray freeze dried micropellet based formulation proof-of-concept for a yellow fever vaccine candidate

“…To reduce cooperative molecular mobility in amorphous solids and improve long-term stability of bioproducts, a convenient way is to increase Tg by introducing polymers. For this work, a list of pharmaceutical additives to examine was chosen using scientific rationale based on literature review [10], [11], [12], [13], [14] and pharmaceutical experience. Sugars selected as bulking agent for this study were sucrose, maltose, trehalose and raffinose.…”

“…An alternative to dextran 10 is PVP 10, which may lead to lower, but still acceptable, mechanical properties (Table 1). PVP-based formulations are used in formulation development [14], [24]. Low molecular weight PVP (grades K12 and K17) are used as solubilizers in parenteral applications, which provide cryo-protection to the product and inhibit potential excipient crystallization [12].…”

“…Low molecular weight PVP (grades K12 and K17) are used as solubilizers in parenteral applications, which provide cryo-protection to the product and inhibit potential excipient crystallization [12]. Similarly, Ficoll® was mentioned to enhance glass transition temperature [14] and maltodextrin was identified as a cryoprotectant excipient for proteins [16], but these components are not available at an excipient grade compatible for parenteral route and other polymers may be preferred. As maltodextrin and CMC-based formulations did not exhibit the best physico-chemical results (F2 to F4 formulation, Table 1), PVP 10 or dextran 10 were selected for further vaccine applications.…”

Formulation strategies in immunotherapeutic pharmaceutical products

“…During the processes, sugars and polyols can exert significant stabilizing effects via mechanisms such as water replacement and vitrification[ 13 ]. Moreover, sugars and polyols act as bulking agent to maintain the integrity of lyophilized “cake” structures[ 14 ].…”

Current Advancements in Addressing Key Challenges of Therapeutic Antibody Design, Manufacture, and Formulation

“…Excipients are considered for a formulation based on their physicochemical properties, pharmacokinetics, and safety. For example, polysorbates are commonly used in biologics as a stabilizing agent; however, their addition in high concentrations can denature proteins and cause adverse side effects such as injection site reactions [114,115,116]. Injectable mAb formulations are co-formulated with recombinant human hyaluronidase, specifically as a permeation enhancer for more efficient absorption into tissue, although the inclusion of this additional biologic adds further burden to the formulation’s viscosity and propensity to aggregate [5,8,25,26,27,28,117,118,119,120,121,122,123].…”