Recent advances in the design and synthesis of prednisolone and methylprednisolone conjugates.

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.

Prednisolone-α-cyclodextrin-star poly(ethylene glycol) polypseudorotaxane with delayed pH-sensitivity as a targeted drug delivery system.

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.

Prednisolone-α-cyclodextrin-star PEG polypseudorotaxanes with controlled drug delivery properties.

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.

Targeted antifungal delivery system: beta-glucosidase sensitive nystatin-star poly(ethylene glycol) conjugate.

A new targeted intravenous conjugate of nystatin with pentaerythritol poly(ethylene glycol)ether has been prepared and characterised (NY(4)-sPEG, M=25 160). The conjugate contains a beta-d-glucopyranoside molecular switch sensitive to beta-glucosidases (E.C.3.2.1.21), which are specifically present in the enzyme outfit of fungal pathogens. The investigated conjugate is stable under in vitro conditions for 24h (solution of phosphate buffer pH=7.4). Spectrophotometrically controlled releasing of nystatin in model medium containing beta-glucosidase ((Aspergillus niger) 2mg/mL, 66.6 units/g; pH 7.4, 2 x 10(-2)M), reported decomposition half-life of conjugate tau(1/2)=(88+/-2)s. This implies that releasing of nystatin is controlled only enzymatically.

New targeting system for antimycotic drugs: beta-glucosidase sensitive amphotericin B-star poly(ethylene glycol) conjugate.

A new targeting potentially intravenous conjugate Amphotericin B (AMB)-star poly(ethylene glycol) (sPEG) (M=25,160) has been synthesized and characterized. It contains a beta-d-glucopyranoside molecular switch which is sensitive to beta-glucosidases (E.C.3.2.1.21). The beta-glucosidase-catalyzed release of AMB from the polymeric carrier was proved in vitro by means of spectrophotometry and HPLC.