Glucocorticoid drugs are commonly used in the treatment of many acute and chronic inflammatory diseases. However, application of these steroids is limited because of their physico-chemical properties, such as very low water solubility. Glucocorticoids also exhibit serious adverse side effects. Therefore, new drug delivery systems are being developed, with the aim of improving the physicochemical properties of glucocorticoids while avoiding undesirable side effects associated with systemic administration. Here we discuss the design and synthesis of conjugates of prednisolone (PD), methylprednisolone (MPD) and similar glucocorticoids. In this review, possibilities for targeting inflammatory sites, and reducing dosages and administration frequency through increasing drug circulation time are discussed. This review summarises synthetic approaches for the preparation of covalent conjugates, which are divided into two groups: low molecular weight conjugates and polymeric conjugates. These two groups are further divided into subgroups based on the chemical structure of the conjugates. Published results from in vitro and in vivo testing of prepared conjugates are also discussed.
- MeSH
- antiflogistika aplikace a dávkování škodlivé účinky chemická syntéza chemie MeSH
- lidé MeSH
- methylprednisolon aplikace a dávkování škodlivé účinky analogy a deriváty chemická syntéza chemie MeSH
- molekulární struktura MeSH
- molekulová hmotnost MeSH
- prednisolon aplikace a dávkování škodlivé účinky analogy a deriváty chemická syntéza chemie MeSH
- prekurzory léčiv aplikace a dávkování škodlivé účinky chemická syntéza chemie MeSH
- racionální návrh léčiv MeSH
- systémy cílené aplikace léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The acylation of prednisolone 20-hydrazone with star poly(ethylene glycol) tetracarboxylic acid (M = 20,000) has been used to prepare the corresponding pH-sensitive conjugate. With α-cyclodextrin, this conjugate forms a polypseudorotaxane, which was characterised by means of (1)H NMR spectra, powder X-ray diffraction patterns and STM microscopy. The rate of acid-catalysed hydrolysis of the conjugate was studied under in vitro conditions in model media of hydrochloric acid solutions, phosphate and acetate buffers (pH 2-5.8). The acid-catalysed hydrolysis (at pH 2) of the polypseudorotaxane was ca 3.5 times slower than that of the original conjugate. After 1h in this medium, 86% of the covalently attached prednisolone remained unchanged. The prepared polypseudorotaxane represents a promising peroral transport system of prednisolone with a pH-sensitive linker with delayed acid-catalysed hydrolysis thanks to protection at the molecular level using α-cyclodextrin.
- MeSH
- alfa-cyklodextriny chemická syntéza chemie farmakokinetika MeSH
- gely MeSH
- glukokortikoidy chemie MeSH
- hydrazony chemie MeSH
- koncentrace vodíkových iontů MeSH
- polyethylenglykoly chemická syntéza chemie farmakokinetika MeSH
- pomocné látky MeSH
- prednisolon analogy a deriváty chemická syntéza chemie farmakokinetika MeSH
- příprava léků metody MeSH
- rotaxany chemie MeSH
- stabilita léku MeSH
- systémy cílené aplikace léků MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The reaction of α-amino-ω-methoxypoly(ethylene glycol) [M = 5000] or star α-amino-poly(ethylene glycol) [M = 20 000] with hemiesters of prednisolone dicarboxylic acids (succinic, glutaric, adipic, phthalic acid) has been used to prepare the corresponding conjugates. The rate of esterase catalyzed hydrolysis of the conjugates is controlled by the molecular mass of poly(ethylene glycol) and the length of the linker between prednisolone and poly(ethylene glycol) (τ(1/2)∼ 5-0.5 h). The enzymatic hydrolysis proceeds most rapidly at conjugates with linkers derived from adipic and phthalic acids. The synthesized conjugates form polypseudorotaxanes with α-cyclodextrin which were characterized by 2D NOESY NMR spectra, powder X-ray diffraction patterns and in one case also by STM microscopy. In the case of the polypseudorotaxane having the linker derived from adipic acid, the enzymatic release proceeds ca. five times slower in comparison with the rate of prednisolone release from the corresponding conjugate. The rate of prednisolone release from the carrier can be controlled by three factors: character of the linker between the polymeric carrier and prednisolone, the molecular mass of poly(ethylene glycol) and complex formation with α-cyclodextrin. The synthesized polypseudorotaxanes represent new promising transport systems intended for targeted release of prednisolone in transplanted liver.
