Prolonged Plasma Levels of Ketoprofen after Oral Administration of Its α-Cyclodextrin Conjugate/Ethylcellulose Dispersion in Rats

6^A-O-[2-(3-benzoylphenyl)propinoyl]--cyclodextrin (KP/-CyD conjugate), in which an anti-inflammatory drug, ketoprofen (KP), is covalently bound to one of the primary hydroxyl groups of -cyclodextrin, was prepared, and the CyD conjugate-based prolonged-release system was designed by combining the KP/-CyD conjugate (used as a delayed-release fraction) with the KP/ethylcellulose (EC) solid dispersion (used as a slow-release fraction). 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 9 h. The co-administration of the conjugate and the EC solid dispersion gave a sustained-release pattern of KP, i.e., a constant plasma KP level was maintained for at least 24 h. The long circulating release patterns in plasma KP levels after oral administration were reflected in the anti-inflammatory effect using with carrageenan-induced acute edema in rat paw.     

Absorption spectra induced by photoexcitation and electrochemical doping in polythiophene

Changes of absorption spectra in a polythiophene film caused by photo- excitation and electrochemical doping are studied. The photoexcitation and the slight doping reveal that the formation of a shallow polaron is responsible to the carrier transport. The doping also induces a deep polaron which can explain the change of spectra upon doping.     

Crystal structures of heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin complexes with (R)- and (S)-Flurbiprofen

Hepatakis(2,3,6-tri-O-methyl)--cyclodextrin (TM--CDx) forms crystalline complexes with (R)-Flubiprofen (R-FP), C₆₃H₁₁₂O₃₅C₁₅H₁₃O₂F·H₂O, and (S)-Flurbiprofen (S-FP), C₆₃H₁₁₂O₃₅C₁₅H₁₃O₂F. The crystal structures were determined by X-ray analysis. Crystals of both compounds are orthorhombic and the space group isP2₁2₁2₁ with cell dimensions:a=15.092(2),b=21.714(3), andc=28.269(4) Å for theR-FP complex, anda=15.271(2),b=21.451(3) andc=27.895(3) Å for theS-FP complex. The macrocyclic ring of TM--CDx is markedly distorted because of the inability to form intramolecular hydrogen bonds and the steric hindrance involving methyl groups. In both complexes, the phenyl group is inserted into the host cavity from the O(2), O(3) side, which is wider than the O(6) side. The biphenyl moiety ofR-FP is fixed in theR-configuration within the host cavity. The phenyl group ofS-FP is disordered, andR-andS-configurations are statistically distributed with equal probability. TM--CDx molecules are stacked along theb axis to form a column structure. The TM--CDx molecule is laterally shifted with respect to the column axis, and a half of the guest molecule protrudes outside from the crevis of the column. The carboxyl group ofR-FP forms a hydrogen bond with water located outside the host cavity, while the carboxyl group ofS-FP is hydrogen-bonded to an oxygen atom of an adjacent TM--CDx. Supplementary Data relating to this article are deposited with the British Library as Supplementary Publication No. SUP 82064 (24 pages).     

Improved stability of Opalmon tablets under humid conditions IV: effect of polysaccharides and disintegrants on the stability and dissolution property of Opalmon tablets

We studied the effects of dextran, dextrin, and disintegrants on the chemical stability of Opalmon tablets containing Limaprost-alfadex (Limaprost/alpha-cyclodextrin complex) and found that the addition of dextran or dextrin significantly improved the chemical stability of Opalmon tablets under high humidity, compared to lactose. We also examined how dextran stabilizes Limaprost in Opalmon tablets and studied the formulation of Opalmon tablets in order to achieve higher chemical stability, rapid dissolution and reduced stickiness. The results suggested that dextran increases stabilization after moisture adsorption by decreasing the dissociation of Limaprost-alfadex to the free drug and alpha-cyclodextrin in the dextran matrix, when compared with the lactose matrix. The stickiness of Opalmon tablets containing dextran and dextrin was negligible when dextran and dextrin amounted to less than 20% of the formulation. By selecting a proper disintegrant, we obtained Opalmon tablets with higher chemical stability and rapid dissolution properties.     

Potential Use of Dendrimer/α-Cyclodextrin Conjugate as a Novel Carrier for Small Interfering RNA (siRNA)

RNA interference (RNAi) is the mechanism of gene silencing-mediated messenger RNA degradation by small interference RNA (siRNA), which becomes a powerful tool for genetic analysis and novel gene therapy. However, one of the major obstacles for siRNA delivery is the difficulty to cross the biological membrane due to its hydrophilicity and high molecular weight. We evaluated the potential use of the starburst polyamidoamine dendrimer (generation 3) conjugate with α-cyclodextrin (α-CyD) having an average degree of substitution of 2.4 (α-CDE conjugate) as a siRNA carrier for RNAi. The ternary complex composed of pGL2 control vector (pDNA)/pGL2 siRNA/α-CDE conjugate showed higher pGL2 siRNA sequence-specific gene silencing effects without off-target effects than those of commercial transfection reagents such as Lipofectamine™2000 (LP), TransFast™ (TF) and Lipofectin™ (LF). These results suggest that α-CDE conjugate has the potential to be a novel carrier for siRNA.     

Prominent Solubilizing Effect of 2-Hydroxypropyl-β-cyclodextrin on a New Thiazolidine Derivative (FPFS-410) with Antidiabetic and Lipid-lowering Activities through Inclusion Complex Formation

2-(N-Cyanoimino)-5-{(E)-4-styrylbenzylidene}-4-oxothiazolidine (FPFS-410) is a newly synthesized thiazolidine derivative having not only antidiabetic but also lipid-lowering activities. However, this compound has an extremely low aqueous solubility (2.8×10⁻⁸ M in phosphate buffer at 25 °C). In this study, we attempted to improve the solubility of FPFS-410 in water, by means of the complexation with 2-hydroxypropyl-β-cyclodextrin (HP-β-CyD). Further, the interaction of FPFS-410 with HP-β-CyD in 50% v/v methanol/water mixed solution was investigated by ultraviolet and ¹H-nuclear magnetic resonance (NMR) spectroscopic methods, because the solubility of FPFS-410 in water was too low to study quantitatively the interaction. The results of the solubility method indicated that HP-β-CyD had a markedly high solubilizing ability to FPFS-410, e.g., the solubility of the compound was increased 200,000-fold by the addition of 40 mM HP-β-CyD. The continuous variation plot of the FPFS-410/HP-β-CyD system in 50% v/v methanol/water solution gave a maximum at a host/guest molar ratio of 1:1. ¹H-NMR spectroscopic studies suggested that the stilbene moiety of FPFS-410 is preferably included in the HP-β-CyD cavity to form the 1:1 complex in 50% v/v methanol/water solution. The present results suggest that HP-β-CyD is useful for improvement of the oral bioavailability of FPFS-410.     

Model Analysis for Oral Absorption of a Drug/Cyclodextrin Complex Involving Competitive Inclusion Complexes

The bioavailability parameters of a drug after oral administration of a preparation containing drug/CyD complexes may be modified by formation of competitive inclusion complexes. In this study, we examined the effects of competitors on drug permeation from its CyD complex through in-vitro artificial membranes and in-situ recirculation conditions, for comparison with the results under in-vivo conditions in the bile duct of cannulated rats. Phenacetin, an antipyretic, was used as a model drug, natural CyDs and maltosyl--CyD as host molecules, and benzoic acid derivatives, sodium taurocholate and acetaminophen as competitors. The in-vitro cellophane membrane permeation rate and the in-situ absorption rate of phenacetin were quantitatively predicted by theoretical calculation using the stability constants of drug/CyD and competitor/CyD complexes when CyD weakly interacts with membrane components in lower CyD concentrations (generally below 10 mM). The in-vivo absorption behavior was only qualitatively reproducible by the theoretical calculation, probably because of various physicochemical and physiological factors affecting the absorption. The present results may be useful not only for prediction of intestinal absorption of drugs from CyD preparations, but also for formulation design of CyD preparations containing multi-components.     

Effects of aging on crystallization, dissolution and absorption characteristics of amorphous tolbutamide-2-hydroxypropyl-beta-cyclodextrin complex

The effects of storage on the crystallization, dissolution and absorption of tolbutamide from amorphous tolbutamide-2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) complex were investigated, in comparison with those of polyvinylpyrrolidone (PVP) solid dispersion. The amorphous solid complex of tolbutamide with HP-beta-CyD and the solid dispersion of tolbutamide with PVP were prepared by a spray-drying method. During storage, a stable form of tolbutamide (form I) was crystallized from the amorphous PVP dispersion, whereas a metastable form of tolbutamide (form II) was crystallized from the HP-beta-CyD complex. The dissolution rate of tolbutamide from both HP-beta-CyD complex and PVP dispersion was significantly faster than that of tolbutamide alone. However, the dissolution rate from the PVP dispersion markedly decreased with storage, because of the formation of slow dissolving form I crystals. On the other hand, the dissolution rate from the HP-beta-CyD complex was only slightly decreased due to the formation of fast dissolving formII crystals. These in vitro dissolution characteristics were clearly reflected in the in vivo absorption of tolbutamide and the glucose plasma level after oral administration in dogs. The results suggested that HP-beta-CyD is useful not only for converting crystalline tolbutamide to an amorphous substance, but also for maintaining the fast dissolution rate of the drug over a long period. Furthermore, the crystallization of drugs from CyD complexes, with storage, seemed to be different from that involving polymer excipients such as PVP.     

Some pharmaceutical properties of 3-hydroxypropyl- and 2,3-dihydroxypropyl-beta-cyclodextrins and their solubilizing and stabilizing abilities

3-Hydroxypropyl- and 2,3-dihydroxypropyl-beta-cyclodextrins (3-HP- and DHP-beta-CyDs) with different degrees of substitution (D.S.) were prepared and their pharmaceutical properties were investigated. The aqueous solubility of 3-HP- and DHP-beta-CyDs was much higher than that of the parent beta-CyD and the dissolution of DHP-beta-CyD in water was endothermic. The acid- and alpha-amylase-catalyzed hydrolysis rates of 3-HP- and DHP-beta-CyDs were slower than those of the parent beta-CyD. The hemolytic activity (human erythrocytes) and local irritancy (rabbit muscle) of DHP-beta-CyD were considerably less than those of natural, methylated or other hydroxyalkylated beta-CyDs, and decreased with increasing D.S. The ability of the hydroxyalkylated beta-CyDs to remove cholesterol and proteins from human erythrocytes decreased with increasing D.S., and correlated well with their hemolytic activity. 3-HP-beta-CyD was a more effective solubilizer for poorly water-soluble drugs than the parent beta-CyD, and its stabilizing effect on chemically instable drugs was higher than that of the parent beta-CyD. The above data suggest a considerable pharmaceutical potential of 3-HP- and DHP-beta-CyDs as parenteral carriers.