Therapeutic formulation, development

Messerer CL, Ramsay EC, Waterhouse D, et al. Liposomal irinotecan formulation development and therapeutic assessment in murine xenograft models of colorectal cancer. Clin Cancer Res 2004 10(19) 6638. 

Excipients are thus one of the three components that in combination produce the medicine that the patient will take. In therapeutic terms, the API is of primary importance because without it there is no treatment and no product. However, in terms of the development and manufacture of the product, all three components are equally important, and we neglect any one of them at our peril. The annals of formulation development in most companies, both large and small, are probably littered with examples where some aspect of one of these three components has been neglected in some way, with unfortunate consequences for the project. The interactions between excipients and the other two components (the API and the manufacturing process), and/or between two or more excipients, are fundamental to the transformation of an API into a medicinal product. 

The use of appropriate analytical techniques during formulation development aids the formulation scientist in determining the degradation products and the rate of formation of those products. Since proteins are complex structures, a combination of techniques must be used to ensure that the formulation scientist is able to assess potential degradation of the protein. This information is critical for the successful development of a therapeutic formulation. 

Much interest has been focused recently on developing delivery systems that deaggregate the powder [63], for this effectively minimizes formulation development work. Some of these systems are extremely complex in operation and may prove difficult to achieve in everyday operations. In addition, some designs that have already been achieved (e.g., Nektar Therapeutics Enhance ... 

The seemingly endless variation of polypeptides makes them interesting as potential therapeutics, but it also makes them a challenge to develop into products. Each protein is unique, and just as variation from protein to protein affects biologic production and purification, so it is central to the formulation development process. Methods developed for one biopharmaceutical are not always directly applicable to others. Similarly, it is quite likely that a formulation developed for one biopharmaceutical may not provide the same level of stability for a different biopharmaceutical. 

Mammalian cell culture-derived proteins undergo post-translational modifications within the cell before they are secreted into the culture medium. A major posttranslational modification that can impact half-life, bioavailability, and even immunogenicity of therapeutic proteins is glyscoysla-tion." - Due to these potential effects, glycosylation is carefully monitored during cell line selection and process and formulation development. 

In spite of recent developments and research in synthetic polymers applied in pharmaceutical field, biomaterials, particularly polysaccharides like starch, cellulose, gums and mucilages, have a greater role to play in pharmaceutical formulation development. It is concluded from the discussion in this entry that because of some limitations at the molecular level, there is a need to modify the parent structure of starch to make it available for pharmaceutical and other industrial uses. Physically and chemically modified starches showed very promising results in the delivery of therapeutic agents. The modified starches have enormous potential to be used in drug delivery because of its easy modification and biodegradability. 

Hydrogen Exchange Mass Spectrometry as an Emerging Analytical Tool for Stabilization and Formulation Development of Therapeutic Monoclonal Antibodies ... 

Extracted and adapted with permission from Majumdar, R., Middaugh, C.R., Weis, D.D., Volkin, D.B. (2015) Hydrogen-deuterium exchange mass spectrometry as an emerging analytical tool for stabilization and formulation development of therapeutic monoclonal antibodies. Journal of Pharmaceutical Sciences, 104 (2), 327-345. 2014. 

Esfandiary, R., Hayes, D.B., Parupudi, A., et al. (2013) A systematic multitechnique approach for detection and characterization of reversible self-association during formulation development of therapeutic antibodies. 7 Pharm Sci, 102 (9), 3089-3099. 

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