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Biomedical subjects

K Uekama

Publications and source records attributed to K Uekama.

At least 73 records · Page 4Linked to original sources
PubMed1994

Peracylated beta-cyclodextrins as novel sustained-release carriers for a water-soluble drug, molsidomine.

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

Acylation↗
PubMed1994

Characterization of the inclusion mode of beta-cyclodextrin sulfate and its effect on the chlorpromazine-induced hemolysis of rabbit erythrocytes.

The inclusion mode of beta-cyclodextrin sulfate (beta-CyD-sul) with a cationic drug, chlorpromazine, was investigated, and the effect of beta-CyD-sul on the hemolytic activity of chlorpromazine was compared with that of parent beta-CyD. The interaction of beta-CyD-sul with chlorpromazine was weaker than that of parent beta-CyD, probably because of the steric or electrostatic repulsion between anionic sulfate groups and hydrophobic phenothiazine moiety. Spectroscopic studies, including pH- and salt-effects, as well as thermodynamic parameters, suggested that both electrostatic and hydrophobic interactions are operative in the inclusion complexation of beta-CyD-sul with chlorpromazine. The inhibiting effect of parent beta-CyD on the chlorpromazine-induced hemolysis of rabbit erythrocytes was accounted for by the decreased fraction of free drug through the complexation. In the case of beta-CyD-sul, the hemolysis and binding of the drug to the erythrocyte membrane was higher than those estimated from the fraction of free drug, probably due to the increased hydrophobicity of the drug through the complexation. However, the chlorpromazine-induced shape change of the erythrocytes was significantly suppressed by beta-CyD-sul, and its inhibiting effect was greater than that of beta-CyD, because of the counterbalance of the opposite effects, i.e., internalization and externalization induced by chlorpromazine and beta-CyD-sul, respectively.

Animals↗
PubMed1993

Preparation of heptakis(2,6-di-O-ethyl)-beta-cyclodextrin and its nuclear magnetic resonance spectroscopic characterization.

Heptakis(2,6-di-O-ethyl)-beta-cyclodextrin (DE-beta-CyD) was prepared and its 1H and 13C nuclear magnetic resonance (NMR) signals in DMSO-d6 were unequivocally assigned by two-dimensional COSY and ROESY. The results on 1H coupling constants indicated that all ethylated glucose units are in a 4C1 chair conformation. The average spin-lattice relaxation times (T1) of ring carbons of DE-beta-CyD were only slightly shorter, and their standard deviations from the mean T1 value were larger, than those of beta-cyclodextrin (beta-CyD) and heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD), suggesting the presence of slightly irregular internal motion in the ethylated glucose units. The temperature dependence of chemical shift of DE-beta-CyD in DMSO-d6 suggested that the C3 hydroxyl protons may participate as proton donor in the intramolecular hydrogen bond to the C2 ethoxyl groups of neighboring glucose, and the intramolecular hydrogen bond of DE- and DM-beta-CyDs is much stronger than that of beta-CyD, suggesting the stable macrocyclic ring structure of DE-beta-CyD.

Chemical Phenomena↗
PubMed1993

Design and in-vitro evaluation of a modified-release oral dosage form of nifedipine by hybridization of hydroxypropyl-beta-cyclodextrin and hydroxypropylcellulose.

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-beta-cyclodextrin (HP-beta-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-beta-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 degrees C, 75% r.h.). The present results suggest that a combination of HP-beta-CyD, HCO-60 and HPCs can serve as a modified-release carrier for poorly water-soluble nifedipine.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1993

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

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.

Animals↗
PubMed1993

Inclusion complexation of p-hydroxybenzoic acid esters with 2-hydroxypropyl-beta-cyclodextrins. On changes in solubility and antimicrobial activity.

To obtain a transparent and effective solution of p-hydroxybenzoic acid esters (parabens), the use of 2-hydroxypropyl-beta-cyclodextrins (2-HP-beta-CyDs) as solubilizers with different degrees of substitution (D.S.) was surveyed. 2-HP-beta-CyDs significantly increased the aqueous solubility of four kinds of parabens (methyl < ethyl < propyl < butyl esters), where the solubilizing ability decreased with an increase in the D.S. of the 2-hydroxypropyl group in beta-CyD. The antimicrobial activity of the parabens tended to decrease by complexation with 2-HP-beta-CyDs. However, the activity could be maintained by lengthening the alkyl chain of the parabens. 1H- and 13C-nuclear magnetic resonance and circular dichroism spectroscopic studies suggest that the hydrophobic alkyl moiety of butyl paraben is preferably included in the cavity, and the phenol group extrudes from the cavity. The present results suggest that a suitable combination of 2-HP-beta-CyDs and hydrophobic, longer alkyl parabens is useful for the preservation of liquid formulations.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1992

Prominent inclusion effect of dimethyl-beta-cyclodextrin on photoisomerization of the thromboxane synthetase inhibitor (E)-4-(1-imidazoylmethyl)cinnamic acid.

The direct photoisomerization of (E)-4-(1-imidazoylmethyl)-cinnamic acid (IMC), a thromboxane synthetase inhibitor, to its (Z)-isomer at pH 2.0 was decelerated by beta-cyclodextrin (beta-CyD) and heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD). The photostationary composition [(Z)-isomer:IMC ratio] was shifted in favor of IMC. These effects were much greater with DM-beta-CyD than with the parent beta-CyD. The quantum yield of the photoisomerization was significantly decreased by complex formation with beta-CyDs, whereas the extinction coefficient of the guest was only slightly decreased. This situation was in sharp contrast to those observed in less polar solvents and suggests that the suppressing mechanism with beta-CyD is different from that with less polar solvent systems. Spectroscopic studies (ultraviolet, circular dichroism, and nuclear magnetic resonance) indicated that IMC is tightly included in an axial mode in the cavity of DM-beta-CyD and that the rotation of the photoreactive site is sterically hindered. The results suggest that the suppressing effect of beta-CyDs on the photoisomerization of IMC results mainly from a steric origin.

Cyclodextrins↗
PubMed1992

Acid-catalyzed hydrolysis of maltosyl-beta-cyclodextrin.

Maltosyl-beta-cyclodextrin was hydrolyzed via two pathways in acidic solution: (1) ring opening to give noncyclic oligosaccharides and (2) cleavage of maltose in the branched residue to give glucosyl-beta-CyD and glucose. Ring opening was approximately 2-3 times faster than maltose cleavage because of the multiple hydrolysis sites of the beta-cyclodextrin (beta-CyD) ring (seven glycosidic linkages) compared with only one reaction site of the maltose residue in the branch. Values of the enthalpy and entropy of activation of the hydrolyses were positive and in the range reported for maltose, a result indicating that the hydrolyses proceeded according to the A-1 mechanism (i.e., unimolecular decomposition). The alpha-1,6-glycosidic bond of branched beta-CyDs connecting beta-CyD and branched sugar moieties resisted hydrolysis; this property is a potential pharmaceutical advantage because the parent beta-CyD, which has low aqueous solubility, would not precipitate after hydrolysis.

Cyclodextrins↗
PubMed1992

Enhanced rectal absorption and reduced local irritation of the anti-inflammatory drug ethyl 4-biphenylylacetate in rats by complexation with water-soluble beta-cyclodextrin derivatives and formulation as oleaginous suppository.

To improve the rectal delivery of ethyl 4-biphenylylacetate (EBA), a prodrug of the anti-inflammatory drug 4-biphenylylacetic acid (BPAA), the use of highly water-soluble 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD) was investigated and compared with the use of the parent beta-cyclodextrin (beta-CyD). Among the three beta-CyDs, HP-beta-CyD was best at improving the rectal bioavailability of EBA in rats after single and multiple administrations of oleaginous suppositories (Witepsol H-5) containing the complexes. To gain insight into the enhancing effect of beta-CyDs, the absorption behaviors of EBA (observed by monitoring BPAA as an active metabolite of EBA) and beta-CyDs themselves were examined in vitro, in situ, and in vivo. The in situ recirculation study revealed that the complexed form of EBA was less absorbable from the rectal lumen in the solution state, but this disadvantageous effect of beta-CyDs was compensated in part by the inhibition of the bioconversion of EBA to BPAA. When beta-CyDs were coadministered with EBA in vivo, however, rather high amounts of HP-beta-CyD (approximately 26% of dose) and DM-beta-CyD (approximately 21% of dose), compared with beta-CyD (approximately 5% of dose), were absorbed from the rat rectum. Thus, the enhancement of rectal absorption of EBA in vivo can be explained by the facts that the hydrophilic beta-CyDs increased the release rate of EBA from the vehicle and stabilized EBA in the rectal lumen and that the drug was partly absorbed in the form of the complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Inhibitory effect of 2-hydroxypropyl-beta-cyclodextrin on crystal-growth of nifedipine during storage: superior dissolution and oral bioavailability compared with polyvinylpyrrolidone K-30.

To prevent the crystal-growth of nifedipine during storage, 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) was employed as a hydrophilic drug carrier and compared with polyvinylpyrrolidone K-30 (PVP). Amorphous nifedipine powders were prepared by spray-drying with HP-beta-CyD or PVP, and their crystal-growing behaviour at accelerated storage conditions were examined by X-ray diffraction analysis and microscopy. Although PVP initially retarded the crystallization of nifedipine, it failed to control the increase of crystal size after prolonged storage at 60 degrees C, 75% r.h., resulting in a remarkable decrease in dissolution rate in water. In sharp contrast, a relatively fine and uniform size of nifedipine crystals was maintained in the HP-beta-CyD system even after accelerated storage conditions. The enhanced dissolution observed for all the HP-beta-CyD systems in a dissolution medium containing 0.1% non-ionic surfactant HCO-60 were clearly reflected in the in-vivo absorption of nifedipine following oral administration to dogs. These results suggest that HP-beta-CyD is particularly useful in solving problems encountered on storage of amorphous nifedipine in solid dosage forms.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1992

Improved transdermal delivery of prostaglandin E1 through hairless mouse skin: combined use of carboxymethyl-ethyl-beta-cyclodextrin and penetration enhancers.

The optimal prescription of transdermal preparations of prostaglandin E1 (PGE1) for treatment of peripheral vascular diseases has been investigated. The chemical stability of PGE1 in fatty alcohol/propylene glycol (FAPG) ointment was markedly improved by carboxymethyl-ethyl-beta-cyclodextrin (CME-beta-CyD). Application of a PGE1 ointment containing the penetration enhancer, 1-dodecylazacycloheptane-2-one (Azone) or 1-[2-(decylthio)ethyl]azacyclopentane-2-one (HPE-101), onto the skin of hairless mice showed the increase of blood flow in the skin due to the vasodilating action of PGE1. In particular, the ointment containing a PGE1-CME-beta-CyD complex supplemented with HPE-101 showed the most prominent increase of the blood flow. Compared with other ointments, this ointment was found to show significantly greater transfer of HPE-101 into in-vitro preparations of the skin of hairless mice. Transfer of PGE1 into the skin was thought to be facilitated by this increased transfer of HPE-101. These results suggest that a combination of CME-beta-CyD and HPE-101 is useful for designing PGE1 ointments for topical application with good chemical stability and percutaneous permeability.

Administration, Cutaneous↗
PubMed1992

[Use of water-soluble beta-cyclodextrin derivatives as carriers of anti-inflammatory drug biphenylylacetic acid in rectal delivery].

To improve the rectal delivery of an anti-inflammatory drug, biphenylylacetic acid (BPAA), the use of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and heptakis (2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD) was investigated. Inclusion complex formations of BPAA with both beta-CyDs in a molar ratio of 1:1 in water were ascertained, and their stability constants were determined. The dissolution of BPAA in water and the release of BPAA from an oleaginous suppository (Witepsol H-5) were significantly increased by beta-CyDs, depending on the magnitude of the stability constants of the water-soluble complexes. However, the serum levels of BPAA after rectal administration of the suppositories containing BPAA or its beta-CyDs complexes in rats increased in the order of BPAA alone much less than DM-beta-CyD less than or equal to HP-beta-CyD complex. The in situ recirculation study revealed that the greater the stability constant of the complex, the lesser was the absorption of BPAA from the rectal lumen of rats under the solution state. Both in vivo and in situ studies demonstrated that rather high amount of HP-beta-CyD (about 20% of dose) was absorbable from the rat's rectum, compared with DM-beta-CyD (less than 5% of dose), suggesting the possibility of the permeation of BPAA through the rectal membrane in the form of HP-beta-CyD complex. Furthermore, DM-beta-CyD and HP-beta-CyD significantly reduced the irritation of the rectal mucosa caused by BPAA after the administration of the suppositories to rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Rectal↗
PubMed1992

Inhibitory effect of prostaglandin E1 on laurate-induced peripheral vascular occlusive sequelae in rabbits: optimized topical formulation with beta-cyclodextrin derivative and penetration enhancer HPE-101.

Prostaglandin E1 (PGE1) and its inclusion complexes with beta-cyclodextrin (beta-CyD) and O-carboxymethyl-O-ethyl-beta-cyclodextrin (CME-beta-CyD) were made as topical preparations. The PGE1 preparations, when applied with a penetration enhancer, 1-[2-(decylthio)ethyl]azacyclopentane-2-one (HPE-101), markedly increased the regional blood flow in the ear of rabbits and were longer acting than when administered by the intravenous route. Topical application of the PGE1 preparations significantly protected rabbits against laurate-induced peripheral vascular occlusive sequelae; the protective potency increased in the order of PGE1 alone = beta-CyD complex < CME-beta-CyD complex preparation. The PGE1 preparations elicited skin reactions such as erythema and oedema depending on their vasodilating actions. These reactions disappeared gradually after removal of the preparations, and hence may not be serious obstacles for their safe use. These results suggest that combinations of CME-beta-CyD and HPE-101 work synergistically to facilitate the entry of PGE1 into the skin, and consequently enhance the therapeutic potential of PGE1 in the topical preparation tested.

Administration, Topical↗
PubMed1992

Improvement of oral bioavailability of fenbufen by cyclodextrin complexations.

The interactions of fenbufen (FB) with alpha-, beta-, gamma-cyclodextrins (CyDs) were studied in aqueous solution and in solid state. beta-CyD formed water soluble complex with FB in the molar ratio of 1:2 (guest:host). The solid complex of FB with alpha-CyD was obtained in the molar ratio of 1:2 (guest:host), while the same with gamma-CyD was obtained as 1:1 ratio. The dissolution rate and bioavailability of FB were significantly increased by the formation of inclusion complexes (alpha greater than gamma-CyD complex). CyDs had no effect on the metabolic time of FB forming two active metabolites, and the bioavailability of metabolites was also increased by complexation of FB with CyDs. The bitter taste of FB powder was reduced by alpha-CyD complexation. The enhanced bioavailability and reduced bitterness of FB by CyD complexations suggested the possibility of applying FB in smaller doses with fewer side-effects.

Animals↗
PubMed1991

Crystal structure of 2-O-[(S)-2-hydroxypropyl]cyclomaltoheptaose.

2-O-[(S)-2-Hydroxypropyl]cyclomaltoheptaose crystallises in the monoclinic space group P2(1) with unit-cell dimensions a = 15.072(1), b = 10.409(1), c = 20.623(2) A, and beta = 108.52(1) degrees. The structure was solved by X-ray diffraction and refined to an R-value of 0.096. The macrocyclic ring of the cyclomaltoheptaose moiety is less symmetrical than that in cyclomaltoheptaose. The glucose residue that carries the hydroxypropyl group inclines much more with its primary hydroxyl side towards the inside of the macrocycle than the other glucose residues. The molecules are arranged in a herring-bone fashion to form a cage-type packing structure. The hydroxypropyl group is inserted into the cavity of an adjacent molecule related by a two-fold screw axis, and the hydroxyl group is linked to an HO-6 via OH...water...OH hydrogen bonds. The crystal contains 8.5 water molecules which occupy 11 sites. Two water molecules are included at the primary hydroxyl side of the cyclomaltoheptaose cavity.

Carbohydrate Conformation↗
PubMed1991

Cyclodextrin sulfates: characterization as polydisperse and amorphous mixtures.

Alpha- and beta-cyclodextrins and their hydroxypropyl derivatives were converted by the reaction with chlorosulfonic acid in pyridine to the corresponding sulfates. Cyclodextrin sulfates were shown by fast-atom bombardment mass spectrometry (negative ion mode, triethanolamine matrix) to be mixtures with nearly symmetrical distributions of degree of substitution by sulfate groups and by powder X-ray diffraction to be amorphous. Thus, in these aspects, cyclodextrin sulfates are similar to the potent drug solubilizers hydroxypropylcyclodextrins.

Cyclodextrins↗
PubMed1991

[Improvement of stability and bioavailability of 1-hexylcarbamoyl-5-fluorouracil (HCFU) by O-carboxymethyl-O-ethyl-beta- cyclodextrin].

The possible utility of O-carboxymethyl-O-ethyl-beta-cyclodextrin (CME-beta-CyD) as a novel drug carrier was studied in vitro and in vivo, by using 1-hexylcarbamoyl-5-fluorouracil (HCFU) as a model drug. The chemical instability of HCFU in solution and solid state was improved by CME-beta-CyD complexation. The in vitro release of HCFU from the CME-beta-CyD complex was decelerated in acidic solution, while accelerated at neutral pH regions, showing a typical delayed-release pattern. This pattern was clearly reflected in the blood levels after the oral administration of the complex to dogs, increasing the bioavailability. The present results suggested that CME-beta-CyD is useful as a delayed-release-type carrier for the oral administration of chemically labile HCFU.

Administration, Oral↗