Stability formulation strategies

Formulation strategies for stabilization of proteins commonly include additives such as other proteins (e.g., serum albumin), amino acids, and surfactants to minimize adsorption to surfaces. Modification of protein structure to enhance stability by genetic engineering may also be feasible, as well as chemical modification such as formation of a conjugate with polyethylene glycol. 

A variety of approaches exist for stabilizing proteins, for example, chemical modification, immobilization, and site-directed mutagenesis [95,96], but these techniques are not within the scope of this chapter. The focus here will be on stabilization of proteins via formulation development. The principal formulation strategy is to stabilize the protein using clinically acceptable additives (excipients) or through the use of suitable pharmaceutical-processing technologies. 

Specific formulation strategies need to be employed for macromolecule compounds. An excellent review of protein stability in aqueous solutions has been published by Chi et al. (92). In addition to solution stability of proteins and peptides, aerosolization may result in significant surface interfacial destabilization of these compounds if no additional stabilization excipients are added. This is due to the fact that protein molecules are also surface active and adsorb at interfaces. The surface tension forces at interfaces perturb protein structure and often result in aggregation (92). Surfactants inhibit interface-induced aggregation by limiting the extent of protein adsorption (92). 

At the end I will discuss how the knowledge of the enzymology of the GI tract can be put to good use in devising the essential in vitro tests that are required to screen the stability of potential therapeutic peptides and oligonucleotides and thus help in the development of formulation strategies to protect them. 

The current chapter is intended to provide an overview of the stability problems of biopharmaceuticals and their assessment as well as the formulation approaches that can be used to circumvent these problems. Presented next is a literature review on the known degradation/denaturation mechanisms of various biopharmaceuticals, followed by a general discussion on the formulation strategies using specific excipients/additives for improving the product shelf-life. 

Formulation strategies, such as addition of specific functional excipients, freezedrying, protein engineering, and delivery strategies, have been used to improve the stability and circulation half-life and reduce immunogenicity, which in turn improve... 

Sanchez A, Villamayor B, Guo Y, Mclver J, Alonso MJ. Formulation strategies for the stabilization of tetanus toxoid in poly (lactide-co-glycolide) microspheres. Int J Pharm 1999 185 255-266. 

Although mAbs share high sequence similarity within an immunoglobulin subclass, they can have dramatically different physical and chemical stability properties unique to a specific mAb. Hence, individual formulation strategies are needed to address different types of physical and chemical instabilities observed for different mAbs formulated in various dosage forms [45]. Stabilization strategies... 

Formulation strategies toward poorly soluble and poorly dispersible drugs focus on obtaining as highly dispersed a drug as possible. Such dispersions usually involve stabilization with surface active molecules. Possible dosage forms include lipid-based formulations, nanoparticle preparations, and solid dispersions [7,8,20,21]. 

It is essential to understand the molecular and thermodynamic properties that contribute to the solubility and stability of an ASD. The properties include glass transition temperature, fragility, molecular mobility, devitrification kinetics, and chemical interactions. A thorough understanding of aU of these aspects is imperative for a rational formulation strategy. 

This strategy has resulted in entirely new formulations with remarkable benefits. Sustainable Earth (SE) cleaning products combine reagents determined to be safer for human and environmental health with a positively characterized hybrid surfactant system containing a stabilized oxidizing compound. This system eliminates conventional ingredients such as alkyl glycol ethers, alkali builders, alkylphenol ethoxylates, EDTA and ethanolamine. 

M. A. Hanson and S. K. E. Rouan, Introduction to formulation of protein pharmaceuticals, in Stability of Protein Pharmaceuticals, Part B In Vivo Pathways of Degradation and Strategies for Protein Stabilization (T. J. Ahem and M. C. Manning, eds.), Plenum Press, New York, 1992, pp. 209-233. 

The physical properties of an API can significantly effect the physical and chemical stability of a formulation, its bioavailability and ultimately they can modify the pharmacokinetic profile of the drug. This issue will be discussed in more detail in section 3.4. For these reasons it is necessary to control the physical form of the API at the Pures crystallization step, and throughout the subsequent formulation steps, to ensure a consistent delivery profile to the patient. This control strategy must be documented in the New Drug Application... 

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