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Excipients (Additives) in Parenteral Biologics

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Let’s talk about additives in the parenteral formulation. So, from this slide on, we are going to talk about the formulation of biologics or biological preparations. We use solubility enhancer. We use anti-adsorption agent. We use anti-aggregation agent. We use buffer or buffer components. We use preservatives. We use anti-oxidant. We use osmotic agent. Now solubility enhancer. Now proteins are charge of molecules so they have a tendency to aggregate and precipitate. Because of the intermolecular electrostatic interactions. So in order to break up the aggregation, to prevent the precipitation.
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We need to enhance the solubility and then we can do so by changing the pH; by changing the ionic strength; by addition of amino acids such as lysine or arginine; or by surfactant as such as the dodecylsulfate. Now here let’s look at one example. This example shows the effect of arginine solubility. Now this product or this slide shows the solubility of three TPA formulations in the presence of arginine, the amino acid. And here is the solubility. And the x-axis is the arginine concentration, increasing arginine contrition. And as you can tell, for A, the solubility increases with arginine concentration. So, does C and so does B. So arginine concentration increases the solubility of alteplase, the TPA preparation.
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Let’s look at the Anti-adsorption agent. Now, proteins tend to expose their hydrophobic sites and because of that, that tends to be absorbed or adsorbed onto the surface between the aqueous phase and the plastic container wall. For example, the catheter or the syringes. And therefore we have to use high concentration of albumin which is 1%, as an adsorption or anti-adhesion agent and this is… this works simply by competitive binding with the therapeutic protein, with the albumin. Or we can use lipophilic surfactant with HLB values of less than 6 and that can also prevent adhesion to the interface.
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Or we can use a low concentration of phospholipid, such as lethicin. And that will do the job as well. Let’s look at this example, insulin. Now, this is the hydrophobic surface, of the container, the syringes. For example, now the insulin molecules have a tendency to be adsorbed onto the surface of the hydrophobic surface of the protein. Now when the insulin molecules are polymerized, the situation becomes even worse.

Excipients are an integral part of biological products, used in multiple ways, and have well defined functional roles. These roles include (a) enhancing solubility of the active, (b) enhancing process and shelf life stability of the active, (c) controlling pH and tonicity, (d) maintaining preferred stable conformation for proteins (e) preventing aggregation or degradation of the active, (f) several other functions like bulking agents, antioxidants, or preservatives. Selection and use of the appropriate excipients is crucial in formulating satisfactory therapeutic protein products.

Biologics are inherently unstable and prone to degradation by several physical and chemical degradation mechanisms. Therefore, a variety of excipients are required to stabilize the biologics during processing and storage. These excipients include solubility enhancer, anti-adsorption agent, anti-aggregation agent, buffer components, preservative, anti-oxidant and osmotic agent In this section the effect of arginine on solubility of three TPA formulations is illustrated. In addition, human albumin is demonstrated to reduce aggregation and polymerization of insulin products

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