Tenofovir disoproxil fumarate (TDF, form I) is an orally delivered pharmaceutical salt used for the treatment of HIV and chronic hepatitis, which acts as an inhibitor of nucleotide reverse transcriptase. There are many solid forms of TDF described in the literature; 2 of them were identified in the drug products: form I and form A. It seems that during formulation, the active pharmaceutical ingredient undergoes partial to total conversion of TDF form I to TDF form A. The goals of this study were to investigate when and why did the conversion occur and whether the conversion could be avoided and how. The influence of pH and possible interaction with excipients were studied. The conditions enabling using wet granulation in technology while preventing the undesired conversion were found. The stabilization was achieved either by replacement of used disintegrants or by acid addition to the current composition of formulation.
- MeSH
- difrakce rentgenového záření metody MeSH
- koncentrace vodíkových iontů MeSH
- látky proti HIV chemie metabolismus MeSH
- pomocné látky chemie metabolismus MeSH
- příprava léků metody MeSH
- stabilita léku MeSH
- tenofovir chemie metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of final six propanoyloxy derivatives of 5β-cholan-24-oic acid (tridecafluoroctylsulfanyl- and tridecafluoroctylsulfinylethoxycarbonylpropanoyloxy derivatives) as potential drug absorption promoters (skin penetration enhancers, intestinal absorption promoters) was generated by multistep synthesis. Structure confirmation of all generated compounds was accomplished by (1)H NMR, (13)C NMR, IR and MS spectroscopy methods. All the prepared compounds were analyzed using RP-TLC, and their lipophilicity (RM) was determined. The hydrophobicity (log P), solubility (logS), polar surface area (PSA) and molar volume (MV) of the studied compounds were also calculated. All the target compounds were tested for their in vitro transdermal penetration effect and as potential intestinal absorption enhancers. The cytotoxicity of all the evaluated compounds was evaluated against normal human skin fibroblast cells. Their anti-proliferative activity was also assessed against human cancer cell lines: T-lymphoblastic leukaemia cell line and breast adenocarcinoma cell line. One compound showed high selective cytotoxicity against human skin fibroblast cells and another compound possessed high cytotoxicity against breast adenocarcinoma cell line and skin fibroblast cells. Only one compound expressed anti-proliferative effect on leukaemia and breast adenocarcinoma cells without affecting the growth of normal cells, which should be promising in potential development of new drugs. Most of the target compounds showed minimal anti-proliferative activity (IC50>37μM), indicating they would have moderate cytotoxicity when administered as chemical absorption modifiers. The relationships between the lipophilicity/polarity and the chemical structure of the studied compounds as well as the relationships between their chemical structure and penetration enhancement effect are discussed in this article.
- MeSH
- fibroblasty účinky léků metabolismus MeSH
- fluorované uhlovodíky chemická syntéza metabolismus toxicita MeSH
- hydrofobní a hydrofilní interakce MeSH
- intestinální absorpce MeSH
- kožní absorpce MeSH
- kyseliny cholové chemie MeSH
- lidé MeSH
- membrány umělé MeSH
- MFC-7 buňky MeSH
- permeabilita MeSH
- pomocné látky chemická syntéza metabolismus toxicita MeSH
- proliferace buněk účinky léků MeSH
- propionáty chemická syntéza metabolismus toxicita MeSH
- rozpustnost MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
