Heptakis(2,6-di-O-methyl-3-O-acetyl)-beta-cyclodextrin: A water-soluble cyclodextrin derivative with low hemolytic activity.

Acetyl groups were introduced to the hydroxyl groups of heptakis(2, 6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD), and the resulting heptakis(2,6-di-O-methyl-3-O-acetyl)-beta-CyD (DMA-beta-CyD) was evaluated for the inclusion property and hemolytic activity. It was confirmed by means of NMR and mass spectroscopies that in the DMA-beta-CyD molecule, all seven hydroxyl groups at the 3-position were substituted by acetyl groups. Thus, it has the degree of substitution (DS) of 7, whereas DMA4-beta-CyD with the lower substitution (DS 3.8) was a mixture of components with different DS. The aqueous solubility of DMA-beta-CyD was higher than those of beta-CyD, DM-beta-CyD, and heptakis(2,3,6-tri-O-methyl)-beta-CyD (TM-beta-CyD). The hydrophobicity of the whole molecule, assessed from measurements of surface tension, increased in the order of DM-beta-CyD < DMA-beta-CyD < TM-beta-CyD. The half-life of DMA-beta-CyD for hydrolysis in pH 9.5 and 60 degrees C was about 19 h, and there was only slight liberation of acetic acid in rabbit plasma and carboxylesterase (EC 3.1.1.1) at 37 degrees C. DMA-beta-CyD had an inclusion ability similar to that of TM-beta-CyD for p-hydroxybenzoic acid esters with different alkyl chain lengths and an antiinflammatory drug, flurbiprofen, although it was inferior to that of DM-beta-CyD. The hemolytic activity and rabbit muscular irritation of DMA-beta-CyDs were much weaker than those of DM-beta-CyD: no hemolysis was observed even in the presence of 0.1 M DMA-beta-CyD with DS 7. The results suggest that the water-soluble CyD derivative with superior bioadaptability and inclusion ability can be prepared by properly designing substituents at the 3-position and by optimally controlling their degree of substitution.     

Inclusion complex formation of captopril with alpha- and beta-cyclodextrins in aqueous solution: NMR spectroscopic and molecular dynamic studies

The inclusion complex formation of alpha-cyclodextrin (alpha-CyD), beta-cyclodextrin (beta-CyD), and 2-hydroxylpropyl-beta-cyclodextrin (HP-beta-CyD) with an angiotensin converting enzyme inhibitor, captopril, in aqueous solution was studied by (1)H- and (13)C-nuclear magnetic resonance spectroscopies, including ROESY and GROESY techniques, by kinetic methods and by molecular dynamic calculations. The oxidative degradation of captopril was markedly suppressed in alpha-CyD solutions, whereas beta-CyD and HP-beta-CyD had negligible stabilizing effects. These NMR and kinetic results suggested that alpha-CyD includes preferably the propyl thioalcohol moiety of captopril, depositing the proline moiety outside the cavity. On the other hand, beta-CyD includes a whole molecule of captopril in the cavity, locating the carboxylic acid within the cavity and the terminal thiol moiety outside the cavity. These inclusion structures were supported by molecular dynamic studies.     

Improvement of some pharmaceutical properties of DY-9760e by sulfobutyl ether beta-cyclodextrin

The interaction of DY-9760e, a novel cytoprotective agent, with sulfobutyl ether beta-cyclodextrin (SBE-beta-CyD) in phosphate buffered saline (PBS) at various pH and ionic-strengths was studied by spectroscopic methods and the solubility method, and the results were compared with that of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD). The circular dichroism (CD) spectroscopic studies suggested that both beta-CyDs form the inclusion complexes with DY-9760e in a molar ratio of 1:1, and the interaction of DY-9760e with SBE-beta-CyD is much stronger than that with HP-beta-CyD at any pH studied, in terms of a synergetic effect of hydrophobic and electrostatic interactions. The different intermolecular interaction between the SBE-and HP-beta-CyD complexes was clearly reflected in the stability constant (K'), e.g. the different dependence of K' value on pH and ionic strength of solutions. 1H- and 13C-NMR studies suggested that HP-beta-CyD interacts preferably with the benzene ring of DY-9760e, whereas SBE-beta-CyD interacts not only with the benzene ring via hydrophobic interaction but also with the piperazine ring of the drug via electrostatic interaction. The solubilizing ability of SBE-beta-CyD against DY-9760e was much greater than that of HP-beta-CyD at any pH studied. Furthermore, SBE-beta-CyD markedly suppressed the photo-degradation of DY-9760e in aqueous solution and reduced the adsorption of DY-9760e from PBS to polyvinyl chloride (PVC) tubes after incubation. The results suggest that SBE-beta-CyD is useful in preparing parenteral solutions of poorly water-soluble drugs with positive charge such as DY-9760e.     

Improvement of solubility and oral bioavailability of rutin by complexation with 2-hydroxypropyl-beta-cyclodextrin

The object of this study was to enhance the solubility, dissolution rate, and oral bioavailability of rutin by complexation with 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD). The interaction of rutin with cyclodextrins (CyDs) was evaluated by the solubility, and ultraviolet (UV) and circular dichroism (CD) spectrophotometries. The chemical and enzymatic stability of rutin was examined in an alkaline buffer solution and in rat small intestinal homogenates, respectively. Dissolution rates of rutin and its CyD complexes were measured by the dispersed amount method. In vivo absorption studies of rutin after oral administration via conventional tablet containing rutin alone or its beta-CyD complexes was performed on beagle dogs. The stability constants calculated from the phase solubility method increased in the order of HP-gamma-CyD < G2-beta-CyD < beta-CyD < HP-beta-CyD. Spectroscopic studies also revealed that HP-beta-CyD and beta-CyD formed a relatively more stable inclusion complex with rutin. The dissolution rates of rutin increased by the complexation with CyDs in the order of rutin alone < HP-beta-CyD < or = beta-CyD. HP-beta-CyD inhibited the hydrolysis of rutin in the alkaline buffer solution and the small intestinal homogenates of rats, suggesting that HP-beta-CyD may stabilize rutin in a gastrointestinal tract after oral administration. When the tablet containing rutin or its beta-CyD complexes was administered to beagle dogs, the plasma levels of homovanillic acid (HVA) (a major stable metabolite of rutin) after oral administration of HP-beta-CyD complex were much higher than in either that of rutin alone or in its beta-CyD complex. The in vivo absorption study suggests that HP-beta-CyD increased the oral bioavailability of rutin from the gastrointestinal tracts of beagle dogs because of the increase in solubility, faster dissolution rate, and gastrointestinal stability. HP-beta-CyD has a significant advantage with respect to providing high aqueous solubility while maintaining a lack of toxicity in oral pharmaceutical preparations of rutin.     

Stabilization of isosorbide 5-mononitrate in solid state by β-cyclodextrin complexation

Inclusion complexation of isosorbide 5-mononitrate (5-ISMN) with β-cyclodextrin (β-CyD) was investigated by the solubility method, X-ray diffractometry and thermal analysis. An analysis of the phase solubility diagram indicates that the stoichiometry for the complex of 5-ISMN with β-CyD is 1:1 in the solid state. The volatility of 5-ISMN and the whisker-growth from tablet or powder were significantly retarded by the binding to β-CyD. In addition, the degradation of 5-ISMN stored at 60°C and 75% relative humidity was remarkably inhibited by the β-CyD complexation. The improvement of physicochemical properties of 5-ISMN by β-CyD complexation in the solid state may solve problems encountered by the storage.     

Inclusion complexation of prostaglandin F2 alpha with gamma-cyclodextrin in solution and solid phases

A solid complex of prostaglandin F2 alpha (dinoprost) with gamma-cyclodextrin in a molar ratio of 1:1 was obtained on the basis of the BS-type phase solubility diagram. The mode of interaction in the solid state was studied by powder X-ray diffractometry, thermal analysis, and carbon-13 cross polarization/magic angle spinning nuclear magnetic resonance (13C-CP/MAS-NMR) spectrometry. The X-ray diffraction and NMR data suggested that prostaglandin F2 alpha is included in the cylindrical channels formed by coaxial alignment of gamma-cyclodextrin molecules to give a channel type structure. Dissolution and thermal behaviors of the prostaglandin F2 alpha-gamma-cyclodextrin complex were examined and compared with the drug itself. The result indicated that the gamma-cyclodextrin complex may have great utility as a rapidly dissolving form of prostaglandin F2 alpha with improved thermal stability.     

Improvement of dissolution and absorption characteristics of benzodiazepines by cyclodextrin complexation

Inclusion complexes of 13 benzodiazepines with 3 cyclodextrins (α-, β-, γ-CyDs) in aqueous solution and in the solid phase were studied by solubility methods, spectroscopy (UV, CD, IR), thermal analysis, and X-ray diffractometry, and their modes of interaction were assessed. The importance of the hydrophobicity of the guest molecule and the spatial relationship between host and guest molecules were clearly reflected in the magnitude of the stability constant of the inclusion complexes. The solid complexes of some benzodiazepines with γ-CyD were obtained in a variety of molar ratios, and dissolution and membrane permeation behaviors were examined. The rates of dissolution and permeation of benzodiazepines through a cellophane membrane were significantly increased by γ-CyD complexation. As an example, the rapid dissolving form of diazepam-γ-CyD complex was found to significantly increase the serum levels of drug after oral administration to rabbits.     

Pharmaceutical application of cyclodextrins as multi-functional drug carriers

Owing to the increasingly globalized nature of the cyclodextrin (CyD)-related science and technology, development of the CyD-based pharmaceutical formulation is rapidly progressing. The pharmaceutically useful CyDs are classified into hydrophilic, hydrophobic, and ionic derivatives. Because of the multi-functional characteristics and bioadaptability, these CyDs are capable of alleviating the undesirable properties of drug molecules through the formation of inclusion complexes or the form of CyD/drug conjugates. This review outlines the current application of CyDs in drug delivery and pharmaceutical formulation, focusing on the following evidences. 1) The hydrophilic CyDs enhance the rate and extent of bioavailability of poorly water-soluble drugs. 2) The amorphous CyDs such as 2-hydroxypropyl-beta-CyD are useful for inhibition of polymorphic transition and crystallization rates of drugs during storage. 3) The delayed release formulation can be obtained by the use of enteric type CyDs such as O-carboxymethyl-O-ethyl-beta-CyD. 4) The hydrophobic CyDs are useful for modification of the release site and/or time profile of water-soluble drugs with prolonged therapeutic effects. 5) The branched CyDs are particularly effective in inhibiting the adsorption to hydrophobic surface of containers and aggregation of polypeptide and protein drugs. 6) The combined use of different CyDs and/or pharmaceutical additives can serve as more functional drug carriers, improving efficacy and reducing side effects. 7) The CyD/drug conjugates may provide a versatile means for the constructions of not only colonic delivery system but also site-specific drug release system, including gene delivery. On the basis of the above-mentioned knowledge, the advantages and limitations of CyDs in the design of advanced dosage forms will be discussed.     

Preparation of amorphous indomethacin from aqueous 2,6-di-O-methyl-beta-cyclodextrin solution

The present work was carried out to study the deposition patterns and clearance of technetium-99m (^99mTc) DTPA labeled cromolyn sodium (CS) solutions when administered from two different CS nasal products using gamma scintigraphy. Five healthy volunteers received a single dose with complete crossover design involving treatment A (test formulation) and treatment B (reference formulation). The deposition patterns as well as the changes in distribution of the radiolabeled CS solutions due to the mucociliary transport were monitored by gamma scintigraphy. Primary deposition of the aforementioned nasal solutions occurred in the anterior portion of the nose. After migration into the posterior nasal cavity, the solutions were rapidly cleared by ciliary action into the nasopharynx where it was swallowed. The test product of cromolyn sodium was shown to be equivalent to the reference product with regard to nasal deposition and clearance. The results from this study indicate that external gamma scintigraphy can be used to demonstrate the equivalence of nasal sprays that are intended for local therapeutic action where the drug is not systemically absorbed into the blood circulation. Furthermore, a non-invasive imaging method such as rhinoscintigraphy may prove to be a useful technique to be utilized during the regulatory approval process for local-acting nasal products, and may facilitate the early introduction of these products to the market.     

Improvement of dissolution and absorption characteristics of phenytoin by a water-soluble β-cyclodextrin-epichlorohydrin polymer

Complexes of phenytoin with 3 water-soluble cyclodextrin-epichlorohydrin polymers (α-CyD · EP β-CyD · EP and γ-CyD · EP) in aqueous solution and in the solid phase were studied by a solubility method spectroscopic analyses and X-ray diffractometry. Binding to CyD polymers increased the solubility and dissolution rate of phenytoin in the order of $\text{β-}\text{CyD}\text{·}\text{EP}\text{> α-}\text{CyD}\text{·}\text{EP}\text{≧ γ-}\text{CyD}\text{·}\text{EP}$. The rapidly dissolving form of phenytoin-β-CyD · EP complex was found to significantly increase the plasma levels of the drug after oral administration to dogs. Data are presented suggesting that β-CyD · EP is particularly useful for improving the oral bioavailability of phenytoin.