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Biomedical subjects

K Uekama

Publications and source records attributed to K Uekama.

At least 19 recordsLinked to original sources
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↗
PubMed1990

Slow-release characteristics of diltiazem from ethylated beta-cyclodextrin complexes.

Release characteristics of two ethylated beta-cyclodextrins [heptakis(2,6-di-O-ethyl)-beta-cyclodextrin (diethyl-beta-cyclodextrin) and heptakis(2,3,6-tri-O-ethyl)-beta-cyclodextrin (triethyl-beta-cyclodextrin)] as sustained-release drug carriers were evaluated using diltiazem hydrochloride, a water-soluble calcium antagonist. The release rate of diltiazem from compressed tablets was significantly retarded by the complexation with ethylated beta-cyclodextrin. Various environmental effects (such as pH, rotating speed, and additive in the dissolution medium) on the release rate were investigated, together with a microscopic observation of the tablet surface. The water penetration rate into the tablet was measured in order to gain insight into the release mechanism. The results suggested that diltiazem is released slowly from the hydrophobic matrix consisting of diethyl-beta-cyclodextrin following water penetration. When a single dose of tablets containing diethyl-beta-cyclodextrin complex was orally administered to dogs, the sustained-release pattern of the drug, without decrease in area under the plasma concentration-time curve, was produced for a long period. The release rate of diltiazem can be controlled by combining the ethylated beta-cyclodextrin complexes with the parent beta-cyclodextrin complex in different mixing ratios.

Animals↗
PubMed1990

Design and in vitro evaluation of slow-release dosage form of piretanide: utility of beta-cyclodextrin:cellulose derivative combination as a modified-release drug carrier.

To modify the release rate of piretanide, a potent loop diuretic, a double-layer tablet was designed, and in vitro release was evaluated. For a rapidly releasing portion, hydrophilic beta-cyclodextrin derivatives were employed to form a water-soluble complex with piretanide. For a sustained-release portion, cellulose derivatives were used to provide appropriate hydrophobicity. The release rate of piretanide in the pH range 1.2-6.8 was automatically monitored by a pH-changeable dissolution testing apparatus. The low solubility of piretanide in acidic medium was significantly improved by complexations with dimethyl-beta-cyclodextrin (DM-beta-CyD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CyD). The pH-independent slow release was attained by use of hydroxypropylcellulose (HPC):ethylcellulose (EC) matrices. Then, an optimal formulation of a double-layer tablet was obtained by the combination of each fraction. For example, the tablet consisting of the [DM-beta-CyD/(HPC:EC)] system in the weight ratio [1/3(1:3)] provided a sufficiently slow release of the drug over a period of 8 h in a wide pH region following an initial rapid dissolution.

Cellulose↗
PubMed1990

Enhancement of the antiinflammatory effect of ethyl 4-biphenylyl acetate in ointment by beta-cyclodextrin derivatives: increased absorption and localized activation of the prodrug in rats.

Ethyl 4-biphenylyl acetate (EBA) is a prodrug of the antiinflammatory 4-biphenylyl acetic acid (BPAA). The inclusion complexes of EBA with beta-cyclodextrin (beta-CyD), heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD), and 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) at a molar ratio of 1:2 (EBA:cyclodextrin) were prepared and used to make hydrophilic antiinflammatory ointments. The in vitro release of EBA from the ointments was enhanced by complexation in the order of beta-CyD less than DM-beta-CyD less than or equal to HP-beta-CyD. The improvement correlated with the improved solubility and not with the decreased diffusibility observed to occur upon the complexation of EBA. In vivo the complexation with cyclodextrin derivatives increased both the release of EBA from the vehicle and its conversion in the underlying tissue to BPAA, but the total of EBA and BPAA in the tissue was decreased. In vitro studies confirmed that the effects of cyclodextrin derivatives on the conversion were exerted indirectly. The combination of the enhanced release and of the enhanced prodrug hydrolysis by esterases in the site where the antiinflammatory action is required resulted in increased therapeutic effects. In the model of carrageenan-induced acute edema in rat paw, the complexation improved the therapeutic effects over those of EBA alone in the order of beta-CyD less than DM-beta-CyD less than HP-beta-CyD. HP-beta-CyD may be a particularly useful cyclodextrin derivative since it improves the topical availability and does not irritate tissues.

Animals↗
PubMed1990

Utility of 2-hydroxypropyl-beta-cyclodextrin in an intramuscular injectable preparation of nimodipine.

Possible utility of hydroxyalkylated beta-cyclodextrin (beta-CyD) derivatives as parenteral drug carriers was investigated, using nimodipine, a dihydropyridine derivative with calcium antagonistic action, as a model drug. The aqueous solubility of nimodipine increased linearly with increase in the concentration of hydroxyalkylated beta-CyDs, showing an AL-type phase solubility diagram. The stability constant of nimodipine--hydroxyalkylated beta-CyD complexes was in the order of 2,3-dihydroxypropyl-beta-CyD less than beta-CyD less than 2-hydroxyethyl-beta-CyD less than 3-hydroxypropyl-beta-CyD less than 2-hydroxypropyl-beta-CyD, and the solubilizing ability of the beta-CyDs was also in that order. The results of powder X-ray diffractometry and thermal analysis suggested 1:3 (guest:host) complex formation of nimodipine with 2-hydroxypropyl-beta-CyD in the solid state. The dissolution rate of nimodipine-2-hydroxypropyl-beta-CyD complex was much faster than that of the drug alone. Nimodipine-2-hydroxypropyl-beta-CyD complex gave higher plasma levels of the drug after intramuscular administration to rabbits, i.e., the area under the plasma concentration--time curve and the maximum plasma concentration of the complex were about 2.5 times higher than those of the drug alone. The muscular damage after the injection of nimodipine was reduced by the administration of the complexed form.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1989

Differential effects of alpha-, beta- and gamma-cyclodextrins on human erythrocytes.

Alpha-, beta- and gamma-cyclodextrins are cyclic hexamers, heptamers, and octamers of glucose, respectively, and thus are hydrophilic; nevertheless, they have the ability to solubilize lipids through the formation of molecular inclusion complexes. The volume of lipophilic space involved in the solubilization process increases with the number of glucose units in the cyclodextrin molecule and, consequently, cyclodextrins were found to have different effects on human erythrocytes: (a) in the induction of shape change from discocyte to spherocyte the potency was observed to be alpha greater than gamma, but with beta-cyclodextrin hemolysis occurred before the change was complete; (b) in the increase of fluorescence intensity of 1-anilinonaphthalene-8-sulfonate in cyclodextrin-pretreated membranes, the observed potency was beta much greater than gamma greater than alpha; (c) in the release of potassium and hemoglobin, the potency was beta greater than alpha greater than gamma. The potencies of cyclodextrin for solubilizing various components of erythrocytes were alpha greater than beta much greater than gamma for phospholipids, beta much greater than gamma greater than alpha for cholesterol and beta much greater than gamma greater than alpha for proteins. The solubilization potencies were derived from concentration/final-effect curves. The above processes occurred without entry of solubilizer into the membrane, since (a) beta-[14C]cyclodextrin did not bind to erythrocytes and (b) cyclodextrins did not enter the cholesterol monolayer. A study of the [3H]cholesterol in erythrocytes indicated that beta-cyclodextrin extracted this lipid from membrane into a new compartment located in the aqueous phase which could equilibrate rapidly with additional erythrocytes. Therefore, the effects of cyclodextrins differ from those of detergents which first incorporate themselves into membranes then extract membrane components into supramolecular micelles.

Cyclodextrins↗
PubMed1989

Alkylation of cyclomalto-oligosaccharides (cyclodextrins) with dialkyl sulfate-barium hydroxide: heterogeneity of products and the marked effect of the size of the macrocycle.

The alkylation of cyclomalto-oligosaccharides (cyclodextrins, CDs) with dialkyl sulfate-barium hydroxide has been claimed to yield 2,6-di-O-alkyl derivatives. Re-investigation by plasma desorption-m.s. of the products of laboratory methylation of alpha CD, beta CD, or gamma CD and ethylation of beta CD and several commercial preparations revealed them to be mixtures with broad and roughly symmetrical distributions of the degree of substitution. Recrystallization separated the components only partially. Analysis of the product of methylation of a mixture of CDs established the order of reactivity gamma much greater than alpha greater than or equal to beta. The reactivity of gamma CD thus resembles that of amylose.

Alkylation↗