دانلود رایگان ترجمه مقاله فعل و انفعالات اصلی سورفاکتانت ها در فرمولاسیون پروتئین درمانی (نشریه الزویر ۲۰۱۵)

فعل و انفعالات اصلی سورفاکتانت ها در فرمولاسیون پروتئین درمانی: مروری

Key interactions of surfactants in therapeutic protein formulations: A review

Abstract

Proteins as amphiphilic, surface-active macromolecules, demonstrate substantial interfacial activity, which causes considerable impact on their multifarious applications. A commonly adapted measure to prevent interfacial damage to proteins is the use of nonionic surfactants. Particularly in biotherapeutic formulations, the use of nonionic surfactants is ubiquitous in order to prevent the impact of interfacial stress on drug product stability. The scope of this review is to convey the current understanding of interactions of nonionic surfactants with proteins both at the interface and in solution, with specific focus to their effects on biotherapeutic formulations.

۱ Introduction

Throughout the past decade, there has been a steady increase in the availability of new biological drugs for patients to treat critical and life threatening diseases in various therapeutic areas from oncology to metabolic diseases [1,2]. Correspondingly, there has also been a surge in drug discovery of therapeutic proteins, especially monoclonal antibodies and their related formats such as antibody drug conjugates and bispecific antibodies. It is critical to preserve the stability of any biologic during bioprocessing, drug product manufacturing, transportation, storage, and administration to the patient. Therefore, formulating the protein suitably and optimally requires significant attention to preserve its stability during all possible stresses until it reaches the patient. There are numerous mechanisms that may trigger the formation of aggregates and particles (e.g. hydrophobic association of partially denatured protein, chemical modifications, and interactions with interfaces) [3]. These events may affect the quality of the product and/or increase the level of visible and sub-visible particles beyond the acceptance criteria. The presence of aggregates also raises a concern as a driving factor for immunogenicity; however, to date only chemically modified aggregates of biologics have shown a clear ability to induce anti-drug antibodies in preclinical models [4,5].

One of the major stresses proteins may encounter is interfacial stress (e.g. from air/water interfaces due to mixing of liquid formulations, or ice/water interfaces during freezing/thawing), which if not suitably stabilized generates aggregates or proteinaceous particles [6]. In the absence of stabilizing surfactants and while under stress or long-term storage, fractions of the therapeutic proteins tend to aggregate and/or generate particles [7–۹]. It is in this context that surfactants are prevalently used in the pharmaceutical industry to provide and ensure protein stability, although other excipients (e.g. cyclodextrins) have also shown protection properties [3,10,11]. Certain surfactants, such as polysorbates, have a proven safety profile established by their use as excipients in small molecule drug formulations, acting as solubility enhancers for poorly water-soluble drugs and later used as dispersion stabilizers for nanoparticle formulations [12–۱۸]. The interactions of both ionic and nonionic surfactants with proteins have been reviewed previously [19–۲۱], providing a broad overview. However, the scope of this review is focused on nonionic surfactants and their protection of therapeutic proteins in parenteral formulations, as they play a prominent role as protein stabilizers in commercial formulations, in contrast with ionic surfactants [22,23]. This review will discuss the present state of knowledge of the mode of interaction between proteins and surfactants at air–water and oil–water interfaces, as well as protein–surfactant interactions in solution. Surfactants extensively used in marketed biologics (e.g. polysorbate 20, polysorbate 80, and pluronics (P188)) are the primary emphasis for this discussion.