The oral administration of drugs can induce poor therapeutic effects if they are unable to reach the bloodstream from the intestinal lumen. The poor oral bioavailability of drugs can be associated to their poor dissolution rate in physiologic fluids. Indeed, great amount of drugs are lipophilic, showing high ability to permeate across the intestinal barrier, but their very poor dissolution in water sensibly reduces their oral bioavailability. Deferoxamine is an iron-chelant drug, used in severe forms of Thalassemia, characterized by very poor water solubility and short in vivo half-life. As a consequence, the administration of this drug requires the intravenous way with high frequency, inducing the low compliance of patients. Taking into account that the clusterization can help the dissolution of drugs and protect them from the metabolism, and that can be apply to this drug too1, I have contributed to design a strategy in order to synthetize one omodimer and two omotetramers of deferoxamine (Figure 1). According to this strategy, the drug can be conjugated, through linkers, to cores such as the PWTs (Peptide Welding Technology), currently known to increase the dissolution of some peptides and to reduce their metabolism in the bloodstream, extending their half-time and allowing less administrations2. Preliminary results indicate that the omodimer an omotetramers of deferoxamine obtained with this strategy allow to sensibly increase its dissolution in aqueous medium and to reduce its metabolism in the bloodstream, allowing to extend its half-life and to maintain its chelating properties. Another way to avoid the poor water dissolution of lipophilic drugs is the formulation of pharmaceutical co-crystals, known to potentially induce an increase of their dissolution rate in water with consequent enhancement of oral bioavailability. Very recently it has been demonstrated that co-crystals can also modulate the permeation of drugs across the intestinal barriers3. These aspects will be accurately studied in vitro by using intestinal cells monolayers, in order to verify if co-crystals can be considered as a simple mixture of compounds or a new pharmaceutical and pharmacological entities. REFERENCES [1] Z. Liu, T.-M. Lin, M. Purro, and M. P. Xiong. “Enzymatically Biodegradable Polyrotaxane-Deferoxamine Conjugates for Iron Chelation”, ACS Appl. Mater. Interfaces, 2016, 8, 25788-25797. [2] R. Guerrini, E. Marzola, C. Trapella, M. Pelà, S. Molinari, M.C. Cerlesi, D. Malfacini, A. Rizzi, S. Salvadori, G. Calò. “A novel and facile synthesis of tetra branched derivatives of no-ciceptin/orphanin FQ”, Bioorg. Med. Chem. 2014, 22(14), 3703-3712. [3] A. Dalpiaz, V. Ferretti, G. Botti, B. Pavan, “Drug Release from Pharmaceutical Co-Crystals: Are Therapeutic and Safety Properties of Active Pharmaceutical Substances Retained?”, Curr Drug Deliv. 2019;16(6):486-489.
New strategies to overcome poor oral bioavailability of drugs by increasing their water solubility
Giada Botti
;Denise Bellotti;Alessandro Dalpiaz;Maurizio Remelli;Remo Guerrini
2019
Abstract
The oral administration of drugs can induce poor therapeutic effects if they are unable to reach the bloodstream from the intestinal lumen. The poor oral bioavailability of drugs can be associated to their poor dissolution rate in physiologic fluids. Indeed, great amount of drugs are lipophilic, showing high ability to permeate across the intestinal barrier, but their very poor dissolution in water sensibly reduces their oral bioavailability. Deferoxamine is an iron-chelant drug, used in severe forms of Thalassemia, characterized by very poor water solubility and short in vivo half-life. As a consequence, the administration of this drug requires the intravenous way with high frequency, inducing the low compliance of patients. Taking into account that the clusterization can help the dissolution of drugs and protect them from the metabolism, and that can be apply to this drug too1, I have contributed to design a strategy in order to synthetize one omodimer and two omotetramers of deferoxamine (Figure 1). According to this strategy, the drug can be conjugated, through linkers, to cores such as the PWTs (Peptide Welding Technology), currently known to increase the dissolution of some peptides and to reduce their metabolism in the bloodstream, extending their half-time and allowing less administrations2. Preliminary results indicate that the omodimer an omotetramers of deferoxamine obtained with this strategy allow to sensibly increase its dissolution in aqueous medium and to reduce its metabolism in the bloodstream, allowing to extend its half-life and to maintain its chelating properties. Another way to avoid the poor water dissolution of lipophilic drugs is the formulation of pharmaceutical co-crystals, known to potentially induce an increase of their dissolution rate in water with consequent enhancement of oral bioavailability. Very recently it has been demonstrated that co-crystals can also modulate the permeation of drugs across the intestinal barriers3. These aspects will be accurately studied in vitro by using intestinal cells monolayers, in order to verify if co-crystals can be considered as a simple mixture of compounds or a new pharmaceutical and pharmacological entities. REFERENCES [1] Z. Liu, T.-M. Lin, M. Purro, and M. P. Xiong. “Enzymatically Biodegradable Polyrotaxane-Deferoxamine Conjugates for Iron Chelation”, ACS Appl. Mater. Interfaces, 2016, 8, 25788-25797. [2] R. Guerrini, E. Marzola, C. Trapella, M. Pelà, S. Molinari, M.C. Cerlesi, D. Malfacini, A. Rizzi, S. Salvadori, G. Calò. “A novel and facile synthesis of tetra branched derivatives of no-ciceptin/orphanin FQ”, Bioorg. Med. Chem. 2014, 22(14), 3703-3712. [3] A. Dalpiaz, V. Ferretti, G. Botti, B. Pavan, “Drug Release from Pharmaceutical Co-Crystals: Are Therapeutic and Safety Properties of Active Pharmaceutical Substances Retained?”, Curr Drug Deliv. 2019;16(6):486-489.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
