Protein/excipient system

The mechanism of the protective effects imparted by the excipients has not been fully elucidated. Empirical observations have pointed to the following contributing factors formation of a glassy state of the protein-excipient system crystallinity of the excipients hydrogen bonding between the excipient and protein molecules and residual water content. 

Chemical and aggregation stability of hGH in several other 100% amorphous systems are compared with corresponding stability in pure protein and the glycine mannitol formulation in Figure 5 [38]. Hydroxyethyl starch (HES), stachyose, and trehalose are formulated in a 1 1 weight ratio of excipient hGH, whereas the dextran formulation is 6 1 dextran hGH. While the concept that an excipient system must remain at least partially amorphous to improve protein stability is not in question, it is clear that... 

Proteinaceous active substances are usually formulated in an elaborated excipient system prior to the freeze-drying procedure. Bulking agents, such as mannitol or glycine, are used to increase the bulk volume and provide a suitable matrix in which a small quantity of protein is dispersed [27], Further details regarding use of cryoprotective excipients are described in Sect. 22.2.5. 

Figure 3.9. Generalized overview of the industrial-scale manufacture of recombinant E2 classical swine fever-based vaccine, using insect cell culture production systems. Clean (uninfected) cells are initially cultured in 500-1000 litre bioreactors for several days, followed by viral addition. Upon product recovery, viral inactivating agents such as /i-propiolactone or 2-bromoethyl-iminebromide are added in order to destroy any free viral particles in the product stream. No chromatographic purification is generally undertaken as the product is substantially pure the cell culture media is protein-free and the recombinant product is the only protein exported in any quantity by the producer cells. Excipients added can include liquid paraffin and polysorbate 80 (required to generate an emulsion). Thiomersal may also be added as a preservative. The final product generally displays a shelf-life of 18 months when stored refrigerated...

Type IV poly(ortho esters) are very similar in structure to type II poly(ortho esters), but they do not need to have excipients in the formulation due to the incorporation of no acidic moieties in the polymer backbone (Ng et al. 1997). Rods of poly(ortho ester) loaded with recombinant human-growth hormone and bovine serum albumin have been created. The rods are the products of polymer-protein mixture extrusion at a temperature between 50° and 70°C. Particles have also been produced from these rods (Heller et al. 2000). The size of these particles, >106 pm, was much larger than would be expected to be absorbed by the gastrointestinal lining (Florence 1997). If the particle size can be reduced, this type of polymer system may be made to be acceptable for oral administration. 

Intuitively such delivery systems or excipients would best achieve this objective if they were to be composed of natural products or their modifications an overwhelming presence of excipients under this category (discussed in Ref. 1) provides credence to this observation. The substitution of natural products comprising complex proteins, antibodies, chimera, or toxins in lieu of stand-alone simple inorganic molecules as excipients for parenteral drug delivery represents a paradigm shift in the introduction of emerging excipients in the therapeutic armamentarium. 

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