Sunday, January 4, 2015

To make a simple tablet with a protein as a drug substance is often impossible. Proteins are degrad

Problematic proteins
Proteins are one of the groups of substances that have the greatest potential as future drugs. But proteins are natural interface active, why it is not always an easy task to formulate them as drugs. Read the original article here
By the chemist., PhD stud. Susanne Møllmann1, Ph.D. Jens Thostrup Bukrinsky2, professor, Ph.D. Sven Frøkjær1 and Ph.D. Ulla Elofsson3 1Danmarks Pharmaceutical University, 2Novo Nordisk A / S, 3Ytkemiska Institute AB
To make a simple tablet with a protein as a drug substance is often impossible. Proteins are degraded in the gastrointestinal tract and the tablet precipitate is therefore ineffective if it is taken orally (by mouth). Instead administered vast majority of proteins in the day parenterally (by injection), as for example. precipitate is the case of insulin. Proteins are formulated as a solution, as a suspension or as a lyophilized drug intended for reconstitution prior to use. Many of the proteins that are used today as drugs are substances the body itself forms (eg. Enzymes or hormones) and the medicines have therefore even at low concentrations a very specific effect. Because the low concentrations used, it is essential that the patient receives the desired amount of drug substance and the protein is biologically active. Therefore efforts are the development of the drug to great lengths to ensure the availability of the right amount of active protein in the right place. The work can be made more difficult by the fact that proteins in general have poor chemical and physical stability of the solution, but also of the interaction, for example. precipitate packaging and other interfaces. For injectables are more problematic interfaces in the finished product: liquid-packaging and between precipitate liquid and air. Interaction with the interfaces can change the physical stability of the protein, and this is the reason why adsorption of proteins is an unwelcome phenomenon in the development of new drugs. precipitate
Protein precipitate adsorption to interfaces An interface occurs when two different phases come in contact precipitate with each other. precipitate In order to reduce precipitate the interfacial tension between the two phases searches proteins in solution in many circumstances at such interfaces and accumulate precipitate here (adsorption). This is because proteins are amphiphilic substances with both hydrophilic and hydrophobic amino acids. The interaction between the protein and the interface is usually strongest at very hydrophobic interfaces as air, silicone precipitate or Teflon. Charges respectively. protein and interface also play a crucial role in the strength of the interaction is [1].
Unfolding and aggregation precipitate For the purpose of the adsorption precipitate can occur structural changes in the protein, for example. when it is unfolded as a result of the interaction with the interface. This allows the protein's secondary and tertiary structure is changed, which often leads to changes in the biological activity [2]. At worst unfolding of a few proteins on an interface precipitate having autocatalytic effect on the rest of the proteins in the solution, so the majority of the molecules change structure shortly. This may ultimately lead to the formation of larger aggregates of proteins. Aggregates precipitate are undesirable in injectable pharmaceuticals, not only because they are often biologically inactive, but also because they can clog needles and catheters. It can also cause adverse reactions such. by the body's immune system is activated in response to the unknown form of the protein. It will be a disaster for someone with diabetes.
Studies of protein adsorption studies of protein adsorption to interfaces involves quite special optical techniques. One of these techniques is ellipsometry, wherein the change in the polarization precipitate of elliptically polarized light after reflection precipitate from a surface precipitate is measured (Figure 1). The polarization of the light depends on the surface, the light is reflected from, the refractive index is different for the surfaces with and without the protein. The change in polarization can be translated into a quantitative measure of the amount of adsorbed protein. In Figure 2 an ellipsometry measurement of insulinadsorption to a Teflon-like precipitate surface at pH 7.4. The adsorption proceeds very quickly, suggesting that the insulin has a high affinity to the surface. After approximately 15 min, the amount of adsorbed protein is not further, which means that there is no more insulin available in solution, or that there has been an equilibrium between adsorbed and free insulin. After 60 min, rinsed with buffer, and it gives rise to no desorption. This indicates that the insulin is irreversibly bound to the surface, and that in that case the equilibrium is shifted towards the adsorbed form. Figure 3 shows an adsorption precipitate isotherm of human insulin. At concentrations of 0.1 mg / ml or more, reaching a plateau value for the adsorption of approximately 1.5 mg / m 2. The resulting plateau value is likely to represent a single layer insulin. Insulin in solution is an equilibrium between monomeric, dimeric and hexameric forms of insulin (Figure precipitate 4). Monomeric

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