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10 Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2018 P h a r mTe c h . c o m Developing Technologies cancer types including soft tissue sarcoma, glioblas- toma multiforme, Kaposi's sarcoma, and small-cell lung cancer. Another example, Abraxane (paclitaxel), is an albumin-bound biobetter formulation of paclitaxel that is composed of water-soluble albumin paclitaxel nanoparticles (approximately 130 nm). This formula- tion avoids the need for using solvents, which have been associated with significant toxic side effects, in- cluding hypersensitivity reactions, nephrotoxicity, and neurotoxicity. "Abraxane is approved for the treatment of breast, pancreatic, and non-small cell lung cancer, and is in clinical development for the treatment of melanoma, bladder, and ovarian cancers, and is mar- keted by Celgene," Sleep notes. Biobetter development challenges The development of biobetters, which are meant to be an improvement over the original biologi- cal product they reference by using either an im- proved delivery system, improved formulation, or other modification that enhances efficacy and safety, faces many challenges. One of the more significant challenges is the ability to obtain, and then maintain, a steady therapeutic level of the biologic, Sleep emphasizes. "Albumin does naturally have an extraordinarily long circulatory half-life of three weeks, which can potentially be doubled by the use of albumins with increased affinity for FcRn [neonatal Fc recep- tor]. Hebei Changshan Biochem Pharma Co., Ltd (Changsan), through its collaboration with Con- juChem LLC, is developing a biobetter of Byetta (exendin-4), called albenatide, for the treatment of Type 2 diabetes for the Chinese market through conjugation of exenatide to the free natural thiol conjugation site of albumin. Using the albumin to extend the circulatory half-life of exenatide, al- benatide has an eight-day half-life, significantly reducing dosing frequency from twice daily for Byetta to once a week," Sleep says. An alternative strategy to extend the circulatory half-life of peptide and protein drugs is to develop a genetic fusion to proteins with naturally long plasma half-lives (2). "As described previously, in addition to albumin possessing an extraordinarily long circulatory half-life, albumin is also a very stable protein, which has been employed as an ex- cipient and a manufacturing aid to stabilize bio- logical drugs for many years," Sleep emphasizes. Small angle X-ray diffraction studies (SAXS) have shown that in free solution, the albumin mol- ecules repel each other, offering a possible mecha- nism by which albumin reduces the propensity of the drug to aggregate (3). Stability studies have also shown that albumin fusions have a higher colloidal stability than the original drug. These findings suggest that the beneficial stabilizing properties of albumin observed in free solution can be transferred to an albumin-enabled drug, Sleep explains. He states that "as a clinically proven drug-de- livery platform, albumin offers the f lexibility to associate with, conjugate to, or genetically fuse to proteins, peptides, and small molecules to im- prove the suboptimal performance of the original drug. As a very stable protein, albumin offers the clinically proven potential to develop nanoparticle drug-delivery presentations." He also points out that by improving the charac- teristics of the original reference product by using albumin-based formulation technology, the fea- tures of the resulting biobetter are highly likely to be patentable. Thus, the albumin-based biobetter