Specificity excipients

Freeze-drying is a relatively gentle way of removing water from proteins in solution. However, this process can promote the inactivation of some protein types, and specific excipients (cryopro-tectants) are usually added to the product in order to minimize such inactivation. Commonly used cryoprotectants include carbohydrates (such as glucose and sucrose), proteins (such as HSA), and amino acids (such as lysine, arginine or glutamic acid). Alcohols/polyols have also found some application as cryoprotectants. 

Additionally, the stability of dyes in solution can be dependent upon the specific excipients used in the formulation. For example, FD C Blue 2 was found to fade more rapidly in the presence of several sugars (sorbitol, mannitol, dextrose, sucrose, and lactose) and that the nonionic surfactant Pluronic F-68 promoted the fading of FD C Blue 2. The combination of coloring agents can lead to complications... 

Obviously, each material in a formulation can be characterized in this way by use of instrumented press studies and Ileckel plot analysis in research and development. This approach can be of use to formulators in selecting specific excipients for specific drug entities. However, the characterization and performance of the final formulation are the critical measurements in the scale-up/production compaction operation. 

Very few excipients are manufactured specifically for pharmaceutical use. Manufacturing plants are usually not devoted to the manufacture of a specific excipient. With continuous production cycles, the control and quality are often not at a... 

Presence of specific excipients - evidence that specific excipients may alter dissolution or absorption. 

Since the administration routes are mainly parenteral, the formulation has to be injectable. An injectable formulation requires specific excipients, ways of preparation and formulation types liquid, suspension, or solid formulations. In the development of protein drugs, various formulation principles are used. In Table 5, examples of some of the formulation principles are given. 

To demonstrate that the batch has stability data to support the intended period of use these data can be obtained from actual studies on the specific excipient or from applicable amodel product stability studies that can reasonably be expected to simulate the performance of the specific excipient... 

The current chapter is intended to provide an overview of the stability problems of biopharmaceuticals and their assessment as well as the formulation approaches that can be used to circumvent these problems. Presented next is a literature review on the known degradation/denaturation mechanisms of various biopharmaceuticals, followed by a general discussion on the formulation strategies using specific excipients/additives for improving the product shelf-life. 

Safety issues to be considered are the exact equivalence of the products (especially for biologicals this may pose a problem) and the risk of allergy or intolerance for a specific excipient (e.g. colouring agents). 

The European Pharmacopoeia requires the rabbit pyrogen test for a number of vaccines, some antibiotics, and specific excipients including glucose, if intended for the preparation of large volume parenterals (see Sect. 32.8). These products may be contaminated with pyrogens other than LPS, or are known to inhibit the LAL test. 

The Ph. Eur. monograph Pharmaceutical Preparations, apphcable to both pharmacy preparation and manufacturing, requires that, unless otherwise justified and authorised, the content of specific excipients such as preservatives need to be determined in pharmaceutical preparations. 

Another possibility to adjust the dissolution kinetics is to incorporate specific excipients directly into the extrudate. Water-soluble pore former like mannitol (Deng et al. 2013), citric acid, and sucrose (Schilling et al. 2008) as well as water-soluble polymers like hypromellose, polyethylene oxide (Read et al. 2010), or poloxamers (Zhu et al. 2006) can be extruded together with the API and stabilizing polymer and these have also been shown to improve the dissolution rate. 

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