Iron is an essential element and an important component of every living organism. When people suffer from iron deficiency, a common haematological problem can occur - iron deficiency anemia (IDA).
In third world countries, IDA is frequently linked to malnutrition, in developed countries the most common causes are excessive blood loss, malabsorption and chronic diseases. The treatment of iron deficiency anemia is oral iron replacement therapy, which is affordable and simple. However, this type of treatment can be limited by gastrointestinal side effects and some patients do not respond to treatment. Therefore, parenteral iron preparations have been developed enabling rapid, effective and safe iron substitution.
During our master´s thesis we have compared the stability of second and third generation intravenous iron preparations that are available on the market, and evaluated their safety in vitro. Six different types of parenteral iron formulations have been used in the study. Iron gluconate, iron sucrose and low molecular weight iron dextran belong to the second generation of parenteral iron preparations. Iron carboxymaltose, ferumoxytol and iron (III) isomaltoside 1000 belong to the third generation of parenteral iron preparations. During the study, the stability and degradation rate of iron preparations were analyzed using a reducing agent buffer and acid hydrolysis. We have determined the relative labile iron release in the serum. Furthermore, we have assessed the uptake of iron complexes into mouse monocytes/macrophages. By using a combination of methods, we have tried to illustrate the behavior of iron preparations after their administration. We have also tried to assess whether the prescribed dosing technique is effective and safe.
We found that the choice of carbohydrate ligand in an individual iron complex affects the formulation´s stability, the amount of labile iron and consequently, its toxicity. The relative stability of the iron complex is also affected by the size and molecular weight of the iron complex. Second generation preparations are among the smallest on the market in terms of their size and molecular weight. Our study results coincide with their physicochemical properties – they have lower relative stability of complexes (low thermal stability, fast release profiles), the highest amounts of labile iron, the highest degree of hydrolysis in acid and they show low to moderate uptake into the monocytes/macrophages. Among the iron preparations of the second generation, the iron dextran with low molecular weight is associated with greater relative stability. In terms of size and molecular weight, the iron dextran with low molecular weight is followed by third generation preparations. During the study we have come to the conclusions that indicate their high relative stability (higher thermal stability, slow release profiles), low amounts of labile iron and low degree of hydrolysis in acid. Moreover, ferumoxytol, which has the highest molecular weight, is readily uptaken into monocytes/macrophages. In summary, iron preparations could be classified according to their relative stability of formulation as follows: iron gluconate < iron sucrose << low molecular wieght iron dextran ⡈ iron carboxymaltose ⡈ iron isomaltoside 1000 ⡈ ferumoxytol.
From the results, we can conclude that the obtained in vitro data on iron preparations of the second and third generation confrim the results of clinical studies, that have proven that the products are clinically safe. The obtained results show that taking into acocount the properties of the preparations is very important, when making decisions during therapy. Second generation iron preparations are suitable for longer administration times (between 30 and 60 minutes) in lower single doses, and are therefore more suitable for patients who often visit medical institutions. However, in addition to patient safety and satisfaction, the healthcare system also strives to make these services cost-effective. Consequently, third generation parenteral iron preparations are coming to the fore as they are clinically safe, fast and can replace major iron needs in a single administration.
|
