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Additional Excipients

The buffer component. PH can change or ph change can cause protein aggregation. For example, during the freeze-drying cycle. And therefore maintaining a constant ph is important. And that’s why we use buffer systems. Buffers that contain phosphate, citrate, acetate can be used in the protein formulations. Buffer component also increase solubility. And it enhance stability. Let’s look at this example. This slide shows the pH effect on solubility. Now here you have three formulations of growth hormone. On the x-axis is the ph and on the y-axis is the hormone concentration. And you can tell, at ph 4.5, the growth hormone has the lowest solubility. So ph does affect the solubility of this hormone or biologics in general.
Here is the ph effect on stability. Now here’s the ph on the x-axis, k on the y-axis, by the way, is the degradation constant. And this is the protein. And as you can tell, at ph 7.5 degradation constant is the smallest. So that means at ph 7.5 this protein is the most stable. So ph has an effect on stability. Preservatives. Now single dose injection of the biologics does contain no preservative That is a single dose injection requires no preservative. However, multi-does injection vial injection vials do require preservative. Now, preservatives are bacteriostatic but they are not bactericidal. They don’t kill bacteria. They just inhibit the growth of the bacteria.
Low concentrations of the following compound the Phenylmercuric nitrate, thimerosol, p-hydroxy benzoic acid, those compounds or chemicals at low conditioners are used as preservatives. Antioxidant. Proteins that are rich in methionine, cysteine, trypophan, tyrosine and histidine are subject to oxidative degradation. And therefore we have to use antioxidant such as ascorbic acid, acetylcysteine, EDTA at low concentration to prevent oxidation. Or we can replace oxygen or air with nitrogen in the injection vial, and that will retard the oxidation as well. Osmotic agent. Osmotic agent maintain isotonicity of the parenteral biologic products. They help stabilize the protein structure. And typically, we can use electrolyte as the osmotic agent such as saline. Or we can use a non-electrolyte such as monosaccharide or disaccharide.

An excipient is pharmacologically inert by itself, but when used in combination with an active ingredient provides appreciable benefits. Biological molecules are inherently less stable than small molecules and formulation development is often challenging. Furthermore, complex molecular structure, lack of well-defined stability-indicating assays and a multitude of degradation pathways create major hurdles for the formulation development of biologics. The selection of excipients is crucial to successful development of injectable biologics formulation.

With a growing number of injectable protein therapeutics in development, stabilization during processing and storage presents a major challenge for the biologics formulator Two examples are presented here, one to illustrate the pH effect on solubility of three r-GH formulations, and also on stability of an anti-trypsin antibody. It should be noted that an osmotic agent is often employed to stabilize the tertiary protein structure In addition, a preservative is used for bacteriostatic effect and an antioxidant for prevention of oxidative degradation

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Pharmacotherapy: Understanding Biotechnology Products

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