Fumitoshi Hirayama

Cyclodextrin-based controlled drug release system

Because of their bioadaptability and multi-functional characteristics, cyclodextrins (CDs) are capable of alleviating the undesirable properties of drug molecules in various routes of administration through the formation of inclusion complexes. This article outlines the current application of natural and chemically modified CDs in the design of advanced dosage forms. In an oral drug delivery system (DDS), the hydrophilic and ionizable CDs can serve as potent drug carriers in the immediate release- and delayed release-formulations, respectively, while the release rate of water-soluble drugs can be retarded by hydrophobic CDs. Since CDs are able to extend the function of pharmaceutical additives, the combination of molecular encapsulation with other carrier materials will become effective and a valuable tool in the improvement of drug formulation. Moreover, the most desirable attribute for the drug carrier is its ability to deliver a drug to a targeted site; conjugates of a drug with CDs can be a versatile means of constructing a new class of colon-targeting prodrugs. On the basis of this knowledge, the advantages and limitations of CDs in DDS are addressed.

Inclusi on complexations of steroid hormones with cyclodextrins in water and in solid phase

Abstract Inclusion complexation of 18 steroid hormones with 3 cyclodextrins (α, β- and γ-CyDs) in water and in solid phase were studied by the solubility method, spectroscopies (UV, CD, IR and 1H-NMR), X-ray diffractometry and thermal analysis, and their modes of interactions were assessed. A spatial relationship between host and guest molecules was clearly reflected in the magnitude of the stability constant (γ-> β-> α-CyD) and in the stoichiometry of the inclusion complexes. The 1H-NMR studies including spin-lattice relaxation time and chemical shift measurements suggested that the A-ring of the steroid molecule was predominantly included in the cavity of CyDs. The solid complexes of some steroids with β-and γ-CyDs were obtained generally in the molar ratios of 1:2 and 2:3, respectively, and their dissolution behaviors were examined. The results indicated that the CyD complexes may have a great utility as a rapidly dissolving form of steroids in water.

Improvement of dissolution and absorption characteristics of benzodiazepines by cyclodextrin complexation

Abstract 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.

Improvement of Solubility and Oral Bioavailability of Rutin by Complexation with 2-Hydroxypropyl-β-cyclodextrin

The object of this study was to enhance the solubility, dissolution rate, and oral bioavailability of rutin by complexation with 2-hydroxypropyl-β-cyclodextrin (HP-β-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 β-CyD complexes was performed on beagle dogs. The stability constants calculated from the phase solubility method increased in the order of HP-γ-CyD < G2-β-CyD < β-CyD < HP-β-CyD. Spectroscopic studies also revealed that HP-β-CyD and β-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-β-CyD ≤ β-CyD. HP-β-CyD inhibited the hydrolysis of rutin in the alkaline buffer solution and the small intestinal homogenates of rats, suggesting that HP-β-CyD may stabilize rutin in a gastrointestinal tract after oral administration. When the tablet containing rutin or its β-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-β-CyD complex were much higher than in either that of rutin alone or in its β-CyD complex. The in vivo absorption study suggests that HP-β-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-β-CyD has a significant advantage with respect to providing high aqueous solubility while maintaining a lack of toxicity in oral pharmaceutical preparations of rutin.

Involvement of cholesterol in the inhibitory effect of dimethyl-β-cyclodextrin on P-glycoprotein and MRP2 function in Caco-2 cells

We compared the inhibitory effect of various cyclodextrins (CyDs) on P‐glycoprotein (P‐gp) and multidrug resistance‐associated protein 2 (MRP2) function and examined the contribution of cholesterol to the inhibitory effect of 2,6‐di‐O‐methyl‐β‐cyclodextrin (DM‐β‐CyD) on the efflux activity of the function in Caco‐2 cell monolayers. Of various CyDs, DM‐β‐CyD significantly impaired the efflux activity of P‐gp and MRP2. DM‐β‐CyD released P‐gp and MRP2 from the monolayers in the apical sides transport buffer and decreased the extent of cholesterol as well as P‐gp and MRP2 in caveolae of Caco‐2 cell monolayers, but not caveolin and flotillin‐1. On the other hand, DM‐β‐CyD did not change MDR1 and MRP2 mRNA levels. Therefore, these results suggest that the inhibitory effect of DM‐β‐CyD on P‐gp and MRP2 function, at least in part, could be attributed to the release of these transporters from the apical membranes into the medium as secondary effects through cholesterol‐depletion in caveolae after treatment of Caco‐2 cell monolayers with DM‐β‐CyD.

Inhibitory Effect of 2-Hydroxypropyl-β-cyclodextrin on Crystal-growth of Nifedipine During Storage: Superior Dissolution and Oral Bioavailability Compared with Polyvinylpyrrolidone K-30

Abstract— To prevent the crystal‐growth of nifedipine during storage, 2‐hydroxypropyl‐β‐cyclodextrin (HP‐β‐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‐β‐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°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‐β‐CyD system even after accelerated storage conditions. The enhanced dissolution observed for all the HP‐β‐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‐β‐CyD is particularly useful in solving problems encountered on storage of amorphous nifedipine in solid dosage forms.

In Vitro and In Vivo gene delivery mediated by Lactosylated Dendrimer/α-Cyclodextrin Conjugates (G2) into Hepatocytes

The purpose of this study is to evaluate in vitro and in vivo gene delivery efficiency of polyamidoamine (PAMAM) starburst dendrimer (generation 2, G2) conjugates with alpha-cyclodextrin (alpha-CDE (G2)) bearing lactose (Lac-alpha-CDE) with various degrees of substitution of the lactose moiety (DSL) as a novel hepatocyte-selective carrier in hepatocytes. Lac-alpha-CDE (DSL 2.6) was found to have much higher gene transfer activity than dendrimer, alpha-CDE, Lac-alpha-CDE (DSL 1.2, 4.6, 6.2 and 10.2) and lactosylated dendrimer (Lac-dendrimer, DSL 2.4) in HepG2 cells, which are dependent on the expression of cell-surface asialoglycoprotein receptor (ASGP-R), reflecting the cellular association of the plasmid DNA (pDNA) complexes. The physicochemical properties of pDNA complex with Lac-alpha-CDE (DSL 2.6) were almost comparable to that with alpha-CDE. Lac-alpha-CDE (DSL 2.6) provided negligible cytotoxicity up to a charge ratio of 150 in HepG2 cells. Lac-alpha-CDE (DSL 2.6) provided gene transfer activity higher than jetPEI-Hepatocyte to hepatocytes with much less changes of blood chemistry values 12h after intravenous administration in mice. These results suggest the potential use of Lac-alpha-CDE (DSL 2.6) as a non-viral vector for gene delivery toward hepatocytes.

Characterization of itraconazole/2-hydroxypropyl-β-cyclodextrin inclusion complex in aqueous propylene glycol solution

The interaction of itraconazole, a triazole antifungal agent, with 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) in water and 10% v/v propylene glycol/water solution at pH 2.0 was investigated by the solubility method and ultraviolet and 1H-nuclear magnetic resonance (NMR) spectroscopies. The solubility of itraconazole in water significantly increased as the concentrations of HP-beta-CyD were augmented, showing an AP type phase solubility diagram. The upward curvature closely corresponded to the simulation curve which was calculated on the basis of the 1:2 (guest:host) complexation model. The 1:2 complex was formed even in the presence of 10% v/v propylene glycol, although the co-solvent system made the interaction with HP-beta-CyD weaker due to the competitive inclusion. The ultraviolet spectroscopic studies also supported the 1:2 complex formation of itraconazole with HP-beta-CyD in 10% v/v propylene glycol/water solution at pH 2.0. The 1H-NMR spectroscopic studies suggested that the triazole and triazolone moieties of itraconazole are involved in the 1:2 inclusion complexation.

Cyclodextrin conjugate-based controlled release system: repeated- and prolonged-releases of ketoprofen after oral administration in rats.

6(A)-O-[2-(3-Benzoylphenyl)propinoyl]-alpha-cyclodextrin (KP-alpha-CyD conjugate), in which an anti-inflammatory drug, ketoprofen (KP), is covalently bound to one of the primary hydroxyl groups of alpha-cyclodextrin, was prepared, and its release behavior in vitro and in vivo was investigated. Further, the CyD conjugate-based repeated- and prolonged-release systems were designed by combining the conjugate (used as a delayed-release fraction) with the KP-2-hydroxypropyl-beta-CyD (HP-beta-CyD) complex (used as a fast-release fraction) or with KP-ethylcellulose (EC) solid dispersion (used as a slow-release fraction), respectively. The conjugate released KP only in rat cecum and colonic contents, whereas it was stable in other biological fluids of rats. The conjugate showed a typical delayed-release pattern after oral administration to rats, i.e., plasma levels of KP increased after a lag time of about 3 h and reached a maximum concentration at about 7 h. On the other hand, the non-covalent inclusion complex of KP with HP-beta-CyD gave a rapid increase in plasma drug levels, and the KP-EC solid dispersion retarded slightly the increase of plasma levels. The co-administration of the conjugate and the HP-beta-CyD complex gave a typical repeated release profile, i.e., double peaks were observed at about 1-2 and 8-12 h in plasma KP levels. On the other hand, the co-administration of the conjugate and the EC solid dispersion gave a typical sustained-release pattern of KP, i.e., a constant plasma KP level was maintained for at least 24 h. These repeated or long circulating release patterns in plasma KP levels after oral administration were clearly reflected in the anti-inflammatory effect using rats with carageenan-induced acute edema in paw. The results suggest that various release-controlled preparations can be designed by employing CyD conjugates in combination with other carriers with different releasing properties.

In‐vitro Evaluation of Biphenylyl Acetic Acid‐β‐Cyclodextrin Conjugates as Colon‐targeting Prodrugs: Drug Release Behaviour in Rat Biological Media

Biphenylyl acetic acid was selectively conjugated to one of the primary hydroxyl groups of β‐cyclodextrin through an ester‐ or amide‐linkage, and the physicochemical properties (aqueous solubility and hydrolysis) were investigated.