Haruhisa Ueda

The effect of water-soluble polymers on drug-cyclodextrin complexation

Abstract In aqueous solutions water-soluble polymers were shown to increase the solubilising effect of cyclodextrins on drugs. For example, the solubilising effect of 2-hydroxypropyl-β-cyclodextrin (HPβCD) with molar substitution of 0.6 was improved by 6–57% (on average 27%) when 0.25% (w/v) carboxymethylcellulose was present in the solution and 12–129% (on average 49%) when 0.25% (w/v) polyvinylpyrrolidone (PVP) was present. Similar results were obtained with other cyclodextrins and other polymers. For PVP and 10% (w/v) HPβCD the PVP concentration for maximum solubilisation appeared to be between 0.05 to 0.25% (w/v). At this low concentration PVP had insignificant effect on the viscosity of the aqueous HPβCD solution. The polymers increased the stability constants of the drug-cyclodextrin complexes. Addition of PVP to the aqueous complexation medium resulted in an increased negative enthalpy change, together with an increased negative entropy change.

Physicochemical properties and inclusion complex formation of δ-cyclodextrin

δ-Cyclodextrin (CD) is a cyclic oligosaccharide composed of nine α-1,4-linked d-glucose units. Its physicochemical properties have been characterized only in terms of its X-ray crystal structure (Fujiwara et al., 1990). A method for the purification of δ-CD was examined, and its physicochemical properties and complexation abilities were elucidated and compared with those of α-, β-, and γ-CD (Kobayashi et al., 1986; Miyazawa et al., 1993). Purification of δ-CD from the commercially available CD powder was mainly carried out with the combined treatment of HPLC and column chromatographies. The molecular weight of δ-CD was determined by FAB-MS, and the cyclic structure of δ-CD was identified by 1H-NMR and 13C-NMR. The aqueous solubility of δ-CD was greater than that of β-CD but less than that of α-CD or γ-CD. No surface activity of δ-CD was observed. δ-CD did not exhibit any hemolytic activity at 4.0 × 10−2 M δ-CD, which was close to its saturated solution. The acid-catalyzed hydrolysis increased in the following order: α-CD < β-CD < γ-CD < δ-CD. δ-CD did not show any significant solubilization effect on most of the slightly soluble or insoluble drugs in water. However, in the case of a large guest molecule such as spironolactone (SP) and digitoxin, which have a steroidal framework, the enhancement of solubility of the guest molecule by δ-CD was greater than that by α-CD. The solubility of SP increased about 30-fold in the presence of δ-CD (4.5 × 10−2 M), showing the features of an Al type phase diagram.

An anhydrous polymorphic form of trehalose.

An anhydrous polymorphic form of alpha,alpha-trehalose was prepared from trehalose dihydrate by two different drying methods: (1) heating under vacuum; and (2) heating in hot air. Preparation of this anhydrous form by vacuum heating showed good reproducibility. This form was characterized by X-ray powder diffraction analysis and differential scanning calorimetry. This anhydrous form was converted to an amorphous phase at 127 degrees C and was found to be hygroscopic. At 43% relative humidity at 25 degrees C, this form rapidly reverted to dihydrate, while the amorphous phase remained unchanged. When an amorphous phase coexisted with this form, the rate of water adsorption to the amorphous phase was slower than that to the amorphous phase alone. These properties of this anhydrous form of alpha,alpha-trehalose may explain the effects of trehalose in dehydration tolerance of plants and insects in the desert.

Inclusion complex formation constants of α-, β-, γ-, δ-, ε-, ζ-, η- and θ-cyclodextrins determined with capillary zone electrophoresis

Abstract In contrast to the well known small cyclodextrins (CD), cyclomaltohexaose ( α -CD), cyclomaltoheptaose ( β -CD) and cyclomaltooctaose ( γ -CD), very limited information is available on larger CD and their inclusion complex forming properties. Using capillary electrophoresis, the binding constants of inclusion complexes formed with cyclomaltononaose ( δ -CD), cyclomaltodecaose ( e -CD), cyclomaltoundecaose ( ζ -CD), cyclomaltododecaose ( η -CD) and cyclomaltotridecaose ( θ -CD) and various anions were determined and compared to the corresponding binding constants of α -, β - and γ -CD. All of the large CD were capable to form inclusion complexes. Dependent on the type of guest molecules, δ - and e -CD were the weakest complex formers. The complex forming ability of e , ζ -, η -, and θ -CD increased with increasing size of the ring structure and θ -CD displayed inclusion complex formation constants comparable to γ -CD.

Physicochemical Properties and Complex Formation Abilities of Large-Ring Cyclodextrins

Large-ring cyclodextrins (LR-CD) are cyclic α-1,4-glucanscomposed of nine to more than several hundred glucopyranose units. The firstdefinitive evidence for the existence of LR-CD with a degree of polymerization between 9and 13 was reported in 1965. That LR-CD study did not reveal anything that attracted attention. LR-CD with a degree of polymerization between 9 and 31 were isolated andcharacterized during the past decade, and so began to attract considerable attention. This mini-review summarizes the findings of LR-CD with regard to the potentialfor host-guest interactions and corresponding applications.

Water Soluble Cyclodextrin Polymers: Their Interaction with Drugs

The complex forming ability of a water-soluble β-cyclodextrin epichlorohydrin, polymer (CDPS) and its different molecular weight fractions was studied and compared with the complexing properties of β-cyclodextrin (βCD) and dimethyl-βCD (DM-βCD). CDPS was separated into two main fractions. CDPS and its fractions formed well soluble inclusion compounds with the studied drugs. The low molecular weight fraction formed rather stable complexes with small guest molecules, the high molecular weight fraction was found to be more efficient in binding larger substrates. Structural studies of furosemide-CD complexes were attempted by NMR spectroscopy.

Water solubilization, determination of the number of different types of single-wall carbon nanotubes and their partial separation with respect to diameters by complexation with η-cyclodextrin

Complexation of single-wall carbon nanotubes with 12-membered cyclodextrins enables not only their solubilization in water but also their partial separation with respect to diameters and determination of the number of nanotube types on the basis of NMR spectra.

Interaction between Cycloamylose and Various Drugs

Cycloamylose (CA), has a cyclic structure like cyclodextrin (CD), but has a very large number of molecules, and its physical properties are still unclear. The CA used in this study was supplied by Ezaki Glico Co., Ltd, and was a mixture (mean molecular weight 7720). Predonisolone, cholesterol, digoxin, digitoxin and nitroglycerin were chosen as guest molecules. We evaluated the interaction between CA and the guest molecules using the solubility method described by Higuchi and Connors. The concentration of each dissolved guest molecule was determined by HPLC. This solubility method was performed at a temperature of 5 °C. The phase solubility diagrams of drugs with CA showed type A or type B profiles. Cholesterol, digoxin, digitoxin and predonisolone formed a complex with CA, but nitroglycerin did not.

Stabilization of the lamellar structure of phosphatidylcholine by complex formation with trehalose

Abstract Trehalose (Tre) is found at particularly high concentration in anhydrobiotic organisms, and is effective in stabilizing the bilayer membranes of phospholipids in freeze-drying. We studied the mixture of L -α-dipalmitoylphosphatidylcholine (DPPC) and trehalose at various water contents by differential scanning calorimetry (DSC) and the small angle X-ray diffraction method. The Tre intercalated between lipid bilayers and formed complexes, and the excess Tre crystallized as its dihydrate by the addition of water. The amount of the dihydrate was estimated from the peak area in DSC. The experimental values of the molar ratio (Tre/DPPC) of the complexes thus determined were 1:2 and 1:1, and the corresponding expansions of the lamellar spacing were observed by small angle X-ray diffraction.

Evaluation of a Sulfobutyl Ether β-Cyclodextrin as a Solubilizing/Stabilizing Agent for Several Drugs

To evaluate the potential use of beta-cyclodextrin sulfobutyl ether, 7 sodium salt (SBE7-beta-CD) as a drug solubilizing and stabilizing agent, the solubilizing effects of SBE7-beta-CD on 22 different poorly water-soluble drugs were compared with those of intact beta-CD and heptakis-(2,6-di-O-methyl)-beta-CD (DMCD). SBE7-beta-CD was generally a more effective solubilizer for poorly water-soluble drugs than was intact beta-CD, but SBE7-beta-CD was not as effective as DMCD. The effects of SBE7-beta-CD on the acid hydrolysis rate of prostaglandin I2, the alkaline hydrolysis rate of indomethacin, the dehydration of prostaglandin E1, and the isomerization of prostaglandin A1 were also investigated and compared to those for intact beta-CD, DMCD, and 2,3,6 partially methylated-beta-CD (PMCD). The stabilizing effects of SBE7-beta-CD on chemically unstable drugs were generally higher than those of other CDs.