Daisuke Iohara

Reduction of bitterness of antihistaminic drugs by complexation with β-cyclodextrins.

Reduction of bitterness of antihistaminic drugs by cyclodextrin (CyD) complexation was examined. The stability constant (Kc) of the 1:1 CyD inclusion complexes with antihistaminic drugs increased in the order of 2-hydroxypropyl-β-CyD (HP-β-CyD) ≈ β-CyD > γ-CyD > α-CyD for diphenhydramine and epinastine, and HP-β-CyD ≈ β-CyD > α-CyD > γ-CyD for hydroxyzine, cetirizine, and dl-chlorpheniramine. The inclusion complexes inhibited the adsorption of antihistaminic drugs to lipid membrane using liposomes, as the magnitude of Kc increased. From human gustatory sensation tests, β-CyD and HP-β-CyD potently suppressed the bitterness of antihistaminic drugs in a dose-dependent manner. Further, an artificial taste sensor analysis revealed that β-CyD and HP-β-CyD inhibited the bitterness of antihistaminic drugs in solution. The results suggest that CyDs suppress the bitterness of antihistaminic drugs in solutions through the formation of inclusion complexes. These results may provide useful information for masking or elimination of bitterness of drugs using CyDs.

Evaluation of carboxymethyl-β-cyclodextrin with acid function: Improvement of chemical stability, oral bioavailability and bitter taste of famotidine

The objective of the present study was to evaluate the potential influence of carboxymethyl-beta-cyclodextrin (CM-beta-CyD) on the aqueous solubility, chemical stability and oral bioavailability of famotidine (FMT) as well as on its bitter taste. We examined the effect of the CM-beta-CyD on the acidic degradation of FMT compared with that for sulfobutyl-ether-beta-cyclodextrin (SBE-beta-CyD). The potential use of CM-beta-CyD for orally disintegrating tablets (ODTs) was evaluated in vitro and in vivo. A taste perception study was also carried out. A strong stabilizing influence of CM-beta-CyD was observed against the acidic degradation, in sharp contrast to SBE-beta-CyD which induced a weird destabilizing effect on FMT. (13)C NMR was used to investigate the interaction mode between FMT and the 2 CyDs. In vivo study of ODTs indicated a significant increase in C(max), AUC and oral bioavailability in the case of FMT-CM-beta-CyD tablets, compared with plain drug tablets. However, no significant difference in T(max) and t(1/2) was observed. CM-beta-CyD complexation appears to be an acceptable strategy for enhancing the oral bioavailability of FMT owing to its dramatic effect on the aqueous solubility and chemical stability of the drug. In addition, it has a pronounced effect on masking the bitter taste of FMT.

Formation of stable hydrophilic C60 nanoparticles by 2-hydroxypropyl-β-cyclodextrin.

A number of papers have reported that the large cavity of γ-CyD is favorable for inclusion of C(60) and forms a 1:2 (C(60):γ-CyD) complex, whereas it is thought to be difficult for β-CyD to form a complex at the molecular level. This is because the cavity size of β-CyD (0.78 nm) is smaller than the van der Waals diameter of C(60) (1.0 nm). In this paper, we will report on the formation of the stable C(60) nanoparticles by the hydrophilic 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) layer through weak interaction on the surface of the nanoparticles. C(60) was coground with β-CyD, γ-CyD or HP-β-CyD mainly in a 1:2 molar ratio by an automatic magnetic agitating mortar, the coground powders were dispersed in water, and the resulting solutions were filtered through a pore size of 0.8 μm filter. The γ-CyD and HP-β-CyD systems gave transparent colloidal solutions consisting of C(60)/CyD nanoparticles with the size lower than 100 nm, with high yields (about 100%). The C(60)/HP-β-CyD nanoparticles are physically stable, keeping a small size for more than 28 days, whereas the γ-CyD nanoparticles are readily aggregated to form large particles (>800 nm). Solid and liquid NMR spectroscopic studies including measurements of spin-lattice relaxation times indicated that C(60) interacted with γ-CyD and HP-β-CyD in the solid and colloidal solutions. When compared with the γ-CyD nanoparticles, adsorption studies of a hydrophobic dye on the surface of C(60)/CyD nanoparticles indicated that the surface of the HP-β-CyD nanoparticles is largely covered by HP-β-CyD molecules forming hydrophilic hydration layers. The present results suggest that HP-β-CyD is useful for the preparation of C(60) nanoparticles and medical applications such as photodynamic therapy, in spite of having a cavity size smaller than that of γ-CyD.

Enhancement of the Aqueous Solubility and Masking the Bitter Taste of Famotidine Using Drug/SBE-β-CyD/Povidone K30 Complexation Approach

The objective of the present study was to evaluate the potential of ternary system (comprised of famotidine, beta-cyclodextrin (beta-CyD) or its derivatives and a hydrophilic polymer) as an approach for enhancing the aqueous solubility and masking the bitter taste of famotidine. The aqueous solubility of famotidine increased in the presence of beta-CyDs, particularly sulfobutyl ether beta-CyD (SBE-beta-CyD), and it was further enhanced by the combination of SBE-beta-CyD and polyvinyl pyrrolidone (Povidone) K30. The solid binary (drug-beta-CyDs) and ternary (drug-beta-CyDs-Povidone K30) systems were prepared by the kneading and freeze-drying methods. The dissolution rates of these solid systems were much faster than that of the drug alone. A taste perception study was carried out, initially using a taste sensory machine and subsequently on human volunteers to evaluate the taste masking ability of the ternary complexation. Our results indicated that the combination of SBE-beta-CyD and Povidone K30 is effective not only in the enhancement of the solubility and dissolution rate of famotidine, but also in masking of the bitter taste of the drug. This technique may be of value for the pharmaceutical industries, especially in preparation of rapidly disintegrating tablets dealing with bitter drugs to improve patient compliance and thus effective pharmacotherapy.

Some pharmaceutical and inclusion properties of 2-hydroxybutyl-β- cyclodextrin derivative

2-Hydroxybutyl-β-cyclodextrins (HB-β-CyDs) with different degrees of substitution (D.S.) were prepared and their physicochemical and biological properties and solubilizing abilities were studied and compared with those of 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD). The surface activity of HB-β-CyD was higher than that of HP-β-CyD (D.S. 5.6) and increased with its concentration and D.S. The moisture sorption of HB-β-CyD (D.S. 5.5) was less than that of HP-β-CyD (D.S. 5.6), because of the introduction of hydrophobic hydroxybutyl groups in a molecule. The hemolytic activity (rabbit erythrocytes) decreased in the order of 2,6-di-O-methyl-β-cyclodextrin (DM-β-CyD)>methyl-β-cyclodextrin (M-β-CyD)>HB-β-CyD (D.S. 5.5)>β-CyD>HP-β-CyD (D.S. 5.6). The hemolytic activity of HB-β-CyD increased with D.S. and HB-β-CyD induced echinocyte (or crenation), as well as DM-β-CyD does. It was suggested from the solubility study of membrane components that HB-β-CyD interacted predominantly with cholesterol in erythrocytes, resulting in the hemolysis. The inclusion ability of HB-β-CyD was higher than that of HP-β-CyD (D.S. 5.6), especially for poorly water-soluble drugs with long linear structures such as biphenylylacetic acid and flurbiprofen (FP). For example, HB-β-CyD formed the inclusion complex with FP in a molar ratio of 1:1, by including the biphenyl moiety in the host cavity. The dissolution rate of FP/HB-β-CyD (D.S. 5.5) complex was faster than that of HP-β-CyD (D.S. 5.6) complex. The results suggested that HB-β-CyDs have considerable pharmaceutical potential and can work as a fast-dissolving carrier for poorly water-soluble drugs.

Evaluation of photodynamic activity of C60/2-hydroxypropyl-β-cyclodextrin nanoparticles

The objective of this study is to evaluate the ability of C(60)/2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) naonparticles to generate reactive oxygen species (ROS) and to induce cell toxicity by the photoirradiation. C(60) nanoparticles were prepared by cogrinding with HP-β-CyD for 3 h at 4°C under reduced pressure. The photodynamic activity of C(60)/HP-β-CyD nanoparticles was evaluated by spectroscopic methods, including the electron spin resonance spin-trapping method, and by the cell viability test using Hela cells. C(60)/HP-β-CyD nanoparticles efficiently generated not only superoxide anion radical (O(2)(·-)) and hydroxyl radical (·OH), but also singlet oxygen ((1)O(2)) through photoirradiation. The ROS generation was enhanced by decreasing the mean particle diameter of C(60) nanoparticles, and the particle size smaller than 90 nm showed a high generation of ·OH and (1)O(2). In addition, HP-β-CyD enhanced the generation of (1)O(2), compared with polyvinylpyrrolidone (an effective solubillizer for C(60)), due to partial disposition of C(60) in the hydrophobic CyD cavity. Furthermore, C(60) /HP-β-CyD nanoparticles showed cell toxicity after the light irradiation, but no toxicity was observed without the light irradiation. Therefore, HP-β-CyD is useful for the preparation of stable C(60) nanoparticles with high ROS generation ability, and C(60)/HP-β-CyD nanoparticles are a promising photosensitizer for photodynamic therapy.

Effects of chitosan on oxidative stress and related factors in hemodialysis patients

In recent world-wide studies, chitosans were tested as a dietary supplement for inhibiting the absorption of certain lipids and bile acids. We previously demonstrated the antioxidative and renoprotective potential of chitosan supplementation in chronic renal failure using 5/6 nephrectomized rats. In this study, we report the effects of chitosan on oxidative stress and related factors in hemodialysis patients. The ingestion of chitosan over a 12-week period resulted in a significant decrease in serum indoxyl sulfate and phosphate levels, compared with the levels prior to the start of the study. The ingestion of chitosan also resulted in a lowered ratio of oxidized to reduced albumin and a decrease in the level of advanced oxidized protein products. In in vitro studies, chitosan solutions were found to bind 38.5% of the indoxyl sulfate and 17.8% of the phosphate, respectively. Further, the oxidized albumin ratio was correlated with serum indoxyl sulfate levels in vivo. These results suggest that the ingestion of chitosan results in a significant reduction in the levels of pro-oxidants, which include uremic toxins, in the gastrointestinal tract, thereby inhibiting the subsequent development of oxidative stress in the systemic circulation. In addition, the long-term ingestion of chitosan has the potential for use in treating hyperphosphatemia in hemodialysis patients.

N-acetyl-l-methionine is a superior protectant of human serum albumin against photo-oxidation and reactive oxygen species compared to N-acetyl-l-tryptophan

BACKGROUND Sodium octanoate (Oct) and N-acetyl-l-tryptophan (N-AcTrp) are widely used as stabilizers during pasteurization and storage of albumin products. However, exposure to light photo-degrades N-AcTrp with the formation of potentially toxic compounds. Therefore, we have examined the usefulness of N-acetyl-l-methionine (N-AcMet) in comparison with N-AcTrp for long-term stability, including photo stability, of albumin products. METHODS Recombinant human serum albumin (rHSA) with and without additives was photo-irradiated for 4weeks. The capability of the different stabilizers to scavenge reactive oxygen species (ROS) was examined by ESR spectrometry. Carbonyl contents were assessed by a spectrophotometric method using fluoresceinamine and Western blotting, whereas the structure of rHSA was examined by SDS-PAGE, far-UV circular dichroism and differential scanning calorimetry. Binding was determined by ultrafiltration. RESULTS N-AcMet was found to be a superior ROS scavenger both before and after photo-irradiation. The number of carbonyl groups formed was lowest in the presence of N-AcMet. According to SDS-PAGE, N-AcMet stabilizes the monomeric form of rHSA, whereas N-AcTrp induces degradation of rHSA during photo-irradiation. The decrease in α-helical content of rHSA was the smallest in the presence of Oct, without or with N-AcMet. Photo-irradiation did not affect the denaturation temperature or calorimetric enthalpy of rHSA, when N-AcMet was present. CONCLUSION The weakly bound N-AcMet is a superior protectant of albumin, because it is a better ROS-protector and structural stabilizer than N-AcTrp, and it is probable and also useful for other protein preparations. GENERAL SIGNIFICANCE N-AcMet is an effective stabilizer of albumin during photo-irradiation, while N-Ac-Trp promotes photo-oxidative damage to albumin.

Biomaterials based on freeze dried surface-deacetylated chitin nanofibers reinforced with sulfobutyl ether β-cyclodextrin gel in wound dressing applications.

A freeze-dried gel composed of surface-deacetylated chitin nanofibers (SDACNFs), reinforced with an anionic cyclodextrin, sulfobutyl ether β-cyclodextrin (SBE-β-CD) was evaluated for treating wounds in a rat model, and the results were compared with a SDACNFs gel without SBE-β-CD. The incorporation of prednisolone (PD), a poorly water-soluble drug, in both types of gels and its release from the gels were also compared. In both cases, wound areas were decreased and their effect was higher than that of commercially available wound dressings. The rate of release of PD from the freeze-dried SDACNFs/SBE-β-CD was much faster than that form SDACNFs alone without SBE-β-CD, due to fact that the PD is more soluble in the amorphous SBE-β-CD complex compared to the other preparations. The findings indicate that the freeze-dried SDACNFs/SBE-β-CD gel would be beneficial as a new biomaterial for the treatment of wounds and for preparing homogeneous high-content gels that contain poorly water-soluble drugs.

Antioxidant and renoprotective activity of chitosan in nephrectomized rats.

The effect of chitosan on oxidative stress and chronic renal failure was investigated using 5/6 nephrectomized rats. The ingestion of chitosan over a 4-week period resulted in a significant decrease in total body weight, glucose, serum creatinine and indoxyl sulfate levels (P=0.0011, P=0.0006, P=0.0012, and P=0.0005, respectively), compared with the non-treated nephrectomized group. The ingestion of chitosan also resulted in a lowered ratio of oxidized to reduced albumin (P=0.003) and an increase in biological antioxidant potential (P=0.023). Interestingly, the oxidized albumin ratio was correlated with serum indoxyl sulfate levels in vivo. These results suggest that the ingestion of chitosan results in a significant reduction in the levels of pro-oxidants, such as uremic toxins, in the gastrointestinal tract, thereby inhibiting the subsequent development of oxidative stress in the systemic circulation.