Peracylated β-Cyclodextrins as Novel Sustained-release Carriers for a Water-soluble Drug,Molsidomine

Abstract— Peracylated β-cyclodextrins with different alkyl chains (acetyl-octanoyl) were prepared by acylating all hydroxyl groups of β-cyclodextrin (β-CyD), and their physical properties were evaluated. These hydrophobic β-CyDs decreased the release rate of molsidomine, a peripheral vasodilator, in proportion to the lengthening of alkyl chain and suppressed a peak plasma level of molsidomine following oral administration of peracylated β-CyD complexes to dogs. Among the peracylated β-CyDs tested, perbutanoyl-β-CyD maintained sufficient plasma drug levels for a long period of time, while other peracylated β-CyDs having shorter or longer chains were inappropriate to control the in-vivo release behaviour of molsidomine. The prominent retarding effect of perbutanoyl-β-CyD was ascribable to the appropriate mucoadhesive property and hydrophobicity, compared with other peracylated β-CyDs. The present results suggest that perbutanoyl-β-CyD is particularly useful in modifying the release rate of water-soluble drugs as a novel slow-release carrier.     

In-vivo and in-vitro evaluations of a modified-release oral dosage form of nifedipine by hybridization of hydroxypropyl-β-cyclodextrin and hydroxypropylcelluloses in dogs

Abstract— To maintain a suitable blood level of nifedipine for a long period of time, double-layer tablets consisting of 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) and 3% nonionic surfactant (HCO-60) as a fast-release portion and hydroxypropylcelluloses (HPCs) with different viscosity grades (low, medium and high) as a slow-release portion were prepared, and their in-vitro and in-vivo release behaviours were investigated. Among the seven formulations, the tablet having the mean dissolution time of 0·8–1·3 h gave prolonged plasma nifedipine levels without decrease of AUC after oral administration to dogs. Consequently, the double-layer tablet consisting of HP-β-CyD with 3% HCO-60/(HPC-low: HPC-medium) in a weight ratio 1/(1·5:1·5) was selected as an appropriate modified-release formulation because it elicited almost comparable retarding effects with superior oral bioavailability compared with those of a commercially available slow-release nifedipine product.     

Aluminium β-Cyclodextrin Sulphate as a Stabilizer and Sustained-release Carrier for Basic Fibroblast Growth Factor

Abstract— The water-insoluble aluminium salt of β-cyclodextrin sulphate (Al · β-CyD-Sul) was used as a stabilizer and sustained-release carrier for recombinant human basic fibroblast growth factor (bFGF). An adsorbate of bFGF with Al · β-CyD-Sul was prepared by incubating the protein with a suspension of Al · β-CyD-Sul in water. The mitogenic activity of bFGF released from the adsorbate, as indicated by the proliferation of kidney cells of baby hamster (BHK-21), was almost comparable with that of the intact bFGF. Al-β-CyD-Sul significantly protected bFGF from proteolytic degradation by pepsin and α-chymotrypsin, compared with the water-soluble sodium salt. The in-vitro release of bFGF from the adsorbate was sustained in proportion to a rise in the ratio of Al · β-CyD-Sul to the protein in the adsorbate. Of the bFGF preparations evaluated, the adsorbate of bFGF with Al ·β-CyD-Sul, when given subcutaneously to the rat, showed the most prominent increase in the formation of granulation tissues, due to the stabilization and slow-release of the mitogen. The limited data presented here suggest that the adsorbate of bFGF with Al · β-CyD-Sul has a potent therapeutic efficacy for wound healing, and may be applicable to oral protein formulations for the treatment of intestinal mucosal erosions.     

The expression of mRNA for tumour necrosis factor-α increases in the obstructed kidney of rats soon after unilateral ureteral ligation

Summary: Cytokines, including transforming growth factor (TGF)-β1, contribute to the tubulointerstitial fibrosis of ureteral obstruction. Tumour necrosis factor (TNF)-α, a proinflammatory cytokine produced by multiple cells including macrophages and resident renal cells, has a role in inflammatory cell recruitment in glomerular injury. We measured TNF-α mRNA in the renal cortex of rats at different times after the onset of unilateral ureteral obstruction (UUO) and determined whether angiotensin II (AngII) inhibition or total body irradiation affects the mRNA levels of TNF-α. Rats were killed at 1, 2, 4, 24, 72 and 120h after UUO. Levels of TNF-α mRNA increased significantly in the obstructed kidney at 1h (X 2), 2h (X 2.7), 4h (X 3.6), 24h (X 2.7), 72h (X 1.8) and 120h (X 2.8) after ureteral ligation when compared to the contralateral kidney of the same animals or to control (normal) kidneys. Tumour necrosis factor-α mRNA increased in renal cortical tubules but not in glomeruli. Treatment with enalapril, an angiotensin-converting enzyme (ACE) inhibitor, before and after UUO decreased TNF-α mRNA levels in the obstructed kidney by about 40% at 4h after the onset of UUO, but at 120h there was no difference in TNF-α levels in the obstructed kidney of treated and untreated animals. Total body irradiation, which depletes macrophages in the obstructed kidney, did not prevent the upregulation of TNF-α mRNA expression at 4 h after UUO. Thus, TNF-α may have a role in initiating tubulointerstitial injury in the obstructed kidney. Leucocytes infiltrating the renal interstitium of the obstructed kidney do not appear to contribute to the increased mRNA expression of TNF-α. Angiotensin II may contribute, at least in part, to the early increased expression of TNF-α mRNA in the obstructed kidney.     

In-vivo and In-vitro Correlation for Delayed-release Behaviour of a Molsidomine/O-carboxymethyl-O-ethyl-β-cyclodextrin Complex in Gastric Acidity-controlled Dogs

The in-vivo absorption behaviour of molsidomine from the delayed-release tablets of an O-carboxy-methyl-O-ethyl-β-cyclodextrin complex was investigated using gastric acidity-controlled dogs under fasted and non-fasted conditions. The in-vitro release profiles were generated by changing the pH of the dissolution medium at different rotation paddle speeds. The absorptivity of molsidomine in the high acidity dog was correlated with the pH-changed release profile (pH 1·2 to 7·0 after 2 h), whereas that in the low acidity dog was correlated with the release profile at a constant pH of 7·0. The absorption in fasted dogs was well correlated with the in-vitro release at the low-rotation paddle speed (< 5 rev min^?1), whereas that in the non-fasted dogs was correlated with that of high rotation (100 rev min^?1). The present results suggested that the in-vivo delayed-release behaviour of the complex is predictable from the in-vitro release profiles generated using pH-variable dissolution testing apparatus at different rotation speeds of the paddle.     

Protective effects of cyclodextrin sulphates against gentamicin-induced nephrotoxicity in the rat

Abstract— The effects of cyclodextrin sulphates on the development of rat renal dysfunction induced with gentamicin, an aminoglycoside antibiotic, were studied. Daily subcutaneous injection of gentamicin (100 mg kg^?1, 14 days) developed nephrotoxicity in the rat as assessed by an increase in serum urea nitrogen and histopathological changes in the renal cortex. When cyclodextrin sulphates were given intraperitoneally at 300 mg kg^?1 at 6 h intervals after gentamicin administration, they protected the rat against the drug-induced renal impairment, while the parent cyclodextrins were ineffective. Since post-administration of cyclodextrin sulphates did not reduce the total amount of gentamicin accumulated in the kidney, the protection may occur through interference with intracellular events leading from the drug accumulation to nephrotoxicity. These results suggest that cyclodextrin sulphates are particularly effective in preventing renal failure associated with aminoglycoside treatment.     

Design and In-vitro Evaluation of a Modified-release Oral Dosage Form of Nifedipine by Hybridization of Hydroxypropyl-β-cyclodextrin and Hydroxypropylcellulose

Abstract— To modify the release rate of nifedipine, a potent calcium channel antagonist, a double-layer tablet was designed, anticipating a more balanced oral bioavailability and a prolonged efficacy than the simple plain tablet. Amorphous nifedipine powders prepared by spray-drying with 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) and nonionic surfactant HCO-60 were employed as a fast-release portion to attain an initial rapid dissolution of nifedipine. Hydroxypropylcelluloses (HPCs) with different viscosity grades (type L, M, and H) were used for a slow-release portion to provide an appropriate sustained-release. Taking into account the physiological conditions of the gastrointestinal tract (pH and motility), an optimal formulation of the double-layer tablet was obtained by changing the mixing ratios of each component. For example, the tablet consisting of HP-β-CyD with 3% HCO-60/(HPC-L:HPC-M) in the weight ratio 1/2(1:1) provided a sufficient slow release of the drug over a wide pH region following an initial rapid dissolution. The release of nifedipine from the double-layer tablets was little affected by pH of the medium and rotation speed of paddle after accelerated storage conditions (60°C, 75% r.h.). The present results suggest that a combination of HP-β-CyD, HCO-60 and HPCs can serve as a modified-release carrier for poorly water-soluble nifedipine.