A thermoresponsive hydrophobically modified hydroxypropylmethylcellulose/cyclodextrin injectable hydrogel for the sustained release of drugs.

The objective of this study was to develop a thermoresponsive injectable hydrogel for the sustained release of drugs by taking advantage of host-guest interactions between a hydrophobically modified hydroxypropylmethyl cellulose (HM-HPMC) and cyclodextrin (CD). A thermoresponsive injectable hydrogel was prepared by simply adding CDs to HM-HPMC hydrogel. The HM-HPMC hydrogel was converted into a sol with a low viscosity through host-guest interactions with CDs. The HM-HPMC/ß-CD hydrogel became a gel near body temperature where the host dissociated from the hydrophobic moieties of the polymer in response to the temperature. The yield stress of the HM-HPMC became progressively lower on the addition of ß-CD which was desirable in the case of developing an injectable formulation. When the HM-HPMC/ß-CD hydrogel containing indocyanine green (ICG) was subcutaneously administered to mice, the fluorescence of the ICG remained relatively constant for 24 h after the administration, which was substantially longer than that for ICG alone or an HPMC formulation. The plasma insulin level was maintained for a longer period of time when the HM-HPMC/ß-CD containing insulin was administered and the MRT value was increased by 1.6 times compared to a solution of insulin alone. In addition, the HM-HPMC/ß-CD hydrogel formulation showed a prolonged hypoglycemic effect in response to the insulin which was slowly released from the hydrogel. A thermoresponsive injectable hydrogel was successfully constructed from the highly viscous HM-HPMC and ß-CD, and the resulting formulation functioned as a sustained release carrier for drugs.

Modification of Drug Crystallization by Cyclodextrins in Pre-formulation Study.

Controlling drug crystallization is one of the important issues in pre-formulation study. In recent years, advanced approaches including the use of tailor-made additives have gathered considerable attention to control crystallization behavior of drugs. This review focuses on the use of hydrophilic cyclodextrins (CDs) as additives for controlling drug crystallization. CDs affect the crystallization of drugs in solution and in solid state based on a host-guest interaction. For example, 2,6-di-O-methyl-ß-CD and 2-hydroxybutyl-ß-CD suppressed solution-mediated transition of drugs during crystallization by the host-guest interaction; as a result, metastable forms selectively precipitated in solution. The use of CDs in crystal engineering provided an opportunity for the detection of a new polymorph by changing the crystallization pathway. It was also possible to modify crystal morphology (i.e., crystal habit) by selective suppression of crystal growth on a certain direction based on the host-gust interaction. For solid formulation, stable amorphous drug/CDs complex under humid conditions was prepared using two different CDs. An overview of some recent progress in the use of CDs in crystal engineering and in amorphous formulation is described in this review.

The Use of Enteric Capsules for Releasing a Fragrance over an Extended Period of Time.

A system for releasing a fragrance, citral (CR) over an extended period of time using three types of enteric capsules is reported. The L- and M-type capsules released CR into media with a pH above 6, while the H-type capsule released CR at a pH above 7. The pH of the releasing medium was controlled by sodium borate (SB), i.e., by adding SB-methylcellulose (MC) prepared in different weight ratios (SB-MC 1 : 2, 1 : 1 and 2 : 1) to tablets and by compressing them at different pressures. The tablet containing a large amount of SB and that was pressed at higher pressures permitted the pH of the releasing medium to be changed from 5 to 9, at 4-5 h after the addition of SB to the tablets, while negligible changes were observed for tablets containing low amounts of SB and which were compressed at lower pressures. Reflecting these pH changes, CR was released after different periods of time when SB-MC tablets and capsules containing CR were simultaneously added to the releasing medium. When enteric capsules containing CR and the pH adjusting tablets were simultaneously added to a benzyl acetate (BA) solution, BA was released at a constant rate, while CR was released for different periods of time depending on the type of capsule used. The results suggest that fragrances could be released over different time frames by using enteric capsules and pH adjusting agents, for example, the release of fragrances with sedative effects at night time and with stimulating effects in the morning.

Antioxidant activities of chitosans and its derivatives in in vitro and in vivo studies.

This review focuses on the in vitro and in vivo antioxidant activities of various chitosan preparations, including those with different molecular weights and degrees of acetylation and the nanofibers produced from them. In in vitro studies, low molecular weight (LMW) chitosan with high degrees of deacetylation has more potent antioxidant properties than those of high molecular weight (HMW) chitosan. On the other hand, HMW chitosan has higher adsorption properties than those of LMW chitosan. On the basis of the in vitro results obtained, the ingestion of chitosan and nanofiber derived from it, with moderate MW and degrees of acetylation results in a significant reduction in oxidative stress in several chronic oxidative stress related diseases such as the metabolic syndrome and renal failure. In the future, chitosan and related nanofibers with presumed antioxidant properties may be used as a new source of antioxidant, as a possible food supplement, as an ingredient or in the pharmaceutical industry.

Glucose Responsive Rheological Change and Drug Release from a Novel Worm-like Micelle Gel Formed in Cetyltrimethylammonium Bromide/Phenylboronic Acid/Water System.

A novel glucose (Glc)-responsive gel formed by worm-like micelles (WLMs) has the potential to provide a self-regulating insulin delivery system. We have prepared a WLM gel system using 75 mM cetyltrimethylammonium bromide, 75 mM phenylboronic acid, and water. At pH 9.4, this gel-like system was highly viscous and supported its own weight, and dynamic viscoelasticity measurement indicated that it contained long and entangled WLMs. The visual observation of gels prepared to include >6 mM Glc revealed that these adopted a sol-like appearance, whereas those prepared to include a control compound (2-10 mM diethylene glycol) retained their gel-like appearance. The storage modulus ( G') of this system decreased as the Glc concentration increased (2-10 mM), indicating a gradual shortening of the WLMs. In vitro release was evaluated using a test compound (fluorescein isothiocyanate dextran) in a microsized flow system. By 120 min, the release of this compound from the WLM gel was around 27-fold greater in the presence of 100 mM Glc than without Glc or with 100 mM diethylene glycol. This demonstrated the successful preparation of a WLM gel that showed an altered drug release rate, depending on Glc concentration.

Surface-deacetylated chitin nanofibers reinforced with a sulfobutyl ether ß-cyclodextrin gel loaded with prednisolone as potential therapy for inflammatory bowel disease.

Surface-deacetylated chitin nanofibers (SDACNFs) reinforced with a sulfobutyl ether ß-cyclodextrin (SBE-ß-CD) (NFs-CDs) gel were developed to obtain a controlled release carrier of prednisolone (PD) for the treatment of colitis. PD was released slowly from the gel at both pH 1.2 and 6.8. The in vitro slow release of PD from the NFs-CDs gel was reflected in the in vivo absorption of the drug after oral administration to rats. These results suggest that a simple gel composed of a mixture of SDACNFs and SBE-ß-CD has the potential for use in the controlled release of PD. We also evaluated the therapeutic effects of the NFs-CDs gel containing PD on dextran sulfate sodium (DSS)-induced colitis model mice. The administration of the NFs-CDs gel at intervals of 3days from the beginning of the DSS treatment resulted in a significant improvement, not only in colitis symptoms but also histopathological changes in colon tissue. In addition, the therapeutic effects of the NFs-CDs gel on colitis can be attributed to decreased levels of neutrophil infiltration and the development of oxidative stress. These efficacy profiles of the NFs-CDs gel containing PD suggest that it has the potential for use in the treatment of, not only colitis, but also a variety of other disorders associated with inflammation and oxidative injuries.

Hydrophobically Modified Polymer/α-Cyclodextrin Thermoresponsive Hydrogels for Use in Ocular Drug Delivery.

We report herein on the preparation of thermoresponsive hydrogels by taking advantage of the interaction of cyclodextrins (CDs) and a hydrophobically modified polymer. A hydrophobically modified hydroxypropyl methylcellulose (HM-HPMC) gel formed thermoresponsive hydrogels when small amounts of α-CD were added to the solution. The HM-HPMC/α-CD showed reversible sol-gel transition in the physiological temperature range that was completely opposite to the temperature dependency shown by the original HM-HPMC. The thermoresponsive gelation was attributed to the temperature dependency of the interaction between α-CD and the hydrophobic moiety of HM-HPMC. The potency of the HM-HPMC/α-CD sol-gel transition system in ophthalmic formulation was tested on the eyes of a rabbit. The use of HM-HPMC/α-CD significantly improved the ocular absorption of a drug, diclofenac sodium, by virtue of the rapid formation of a gel on the ocular surface. That is, the HM-HPMC/α-CD was in a low viscous sol state at room temperature, which made administration easy, but it rapidly formed a viscous hydrogel on the ocular surface at physiological temperature. The thermoresponsive hydrogel based on the hydrophobically modified polymer and CD promises to have widespread applications in drug delivery.

An oral absorbent, surface-deacetylated chitin nano-fiber ameliorates renal injury and oxidative stress in 5/6 nephrectomized rats.

In this study, we report that surface-deacetylated chitin nano-fibers (SDACNFs) are more effective in decreasing renal injury and oxidative stress than deacetylated chitin powder (DAC) in 5/6 nephrectomized rats. An oral administration of low doses of SDACNFs (40mg/kg/day) over a 4 week period resulted in a significant decrease in serum indoxyl sulfate, creatinine and urea nitrogen levels, compared with a similar treatment with DAC or AST-120. The SDACNFs treatment also resulted in an increase in antioxidant potential, compared with that for DAC or AST-120. Immunohistochemical analyses also demonstrated that SDACNFs treated CRF rats showed a decrease in the amount of accumulated 8-OHdG compared with the CRF group. These results suggest that the ingestion of SDCH-NF results in a significant reduction in the levels of pro-oxidants, such as uremic toxins, in the gastrointestinal tract, thereby inhibiting the subsequent development of oxidative stress in the systemic circulation.

Biomaterials based on freeze dried surface-deacetylated chitin nanofibers reinforced with sulfobutyl ether ß-cyclodextrin gel in wound dressing applications.

A freeze-dried gel composed of surface-deacetylated chitin nanofibers (SDACNFs), reinforced with an anionic cyclodextrin, sulfobutyl ether ß-cyclodextrin (SBE-ß-CD) was evaluated for treating wounds in a rat model, and the results were compared with a SDACNFs gel without SBE-ß-CD. The incorporation of prednisolone (PD), a poorly water-soluble drug, in both types of gels and its release from the gels were also compared. In both cases, wound areas were decreased and their effect was higher than that of commercially available wound dressings. The rate of release of PD from the freeze-dried SDACNFs/SBE-ß-CD was much faster than that form SDACNFs alone without SBE-ß-CD, due to fact that the PD is more soluble in the amorphous SBE-ß-CD complex compared to the other preparations. The findings indicate that the freeze-dried SDACNFs/SBE-ß-CD gel would be beneficial as a new biomaterial for the treatment of wounds and for preparing homogeneous high-content gels that contain poorly water-soluble drugs.

In Vitro and In Vivo Evaluation of Hydrophilic C60(OH)10/2-Hydroxypropyl-ß-cyclodextrin Nanoparticles as an Antioxidant.

The objective of this study was to assess the antioxidant ability of C60(OH)10/2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) nanoparticles, by comparing their scavenging ability for reactive nitrogen species, their cytoprotective effects under conditions of oxidative stress, and their therapeutic effects against diseases that are induced by oxidative stress. The C60(OH)10/HP-ß-CD nanoparticles had a higher scavenging activity against nitric acid and peroxynitrite (ONOO(-)) than the other antioxidants such as ascorbic acid, trolox, and edaravone. The cytoprotective effect of C60(OH)10/HP-ß-CD nanoparticles was examined on HeLa and HepG2 cells by monitoring the percentage of cell death induced by H2O2. Treatment with C60(OH)10/HP-ß-CD nanoparticles resulted in an increase in cell viability, due to the suppression of the oxidative stress. Furthermore, the nanoparticles had a high cytoprotective effect, compared with other polyhydroxylated C60 (C60(OH)24 and C60(OH)40). The C60(OH)10/HP-ß-CD nanoparticles were intravenously administered to mice with a liver injury induced by an over dose of acetaminophen. Levels of alanine transaminase and aspartate transaminase were essentially the same as those of normal mice and the survival rate was also prolonged by the intravenous administration of the C60(OH)10/HP-ß-CD nanoparticles. The results indicate that C60(OH)10/HP-ß-CD nanoparticles are a promising antioxidant for use in the treatment of diseases caused by oxidative stresses.

Ternary inclusion complex formation and stabilization of limaprost, a prostaglandin E1 derivative, in the presence of α- and ß-cyclodextrins in the solid state.

Limaprost/α-cyclodextrin (CD)/ß-CD ternary inclusion complex was prepared by freeze-drying a solution containing all three components. Under humid conditions, limaprost was more stable in the ternary α-/ß-CD inclusion complex than in the binary α- or ß-CD complex. Specifically, during storage at 30°C/75% relative humidity (R.H.) for 4 weeks, about 19% of limaprost degraded into 17S,20-dimethyl-trans-Δ(2)-prostaglandin A1 (referred as 11-deoxy-Δ(10)) in the ß-CD complex, 8.1% degraded in the α-CD complex, and only 2.2% degraded in the α-/ß-CD complex. The mechanism of limaprost stabilization in the presence of both CDs was investigated by Raman and solid-state NMR spectroscopy and powder X-ray diffractometry. The fast degradation of limaprost to 11-deoxy-Δ(10) in the ß-CD complex was due to the rapid crystallization of ß-CD from the complex, liberating the free amorphous drug, which is susceptible to degradation. The dissociation and crystallization of ß-CD from the inclusion complex were suppressed by freeze-drying limaprost in the presence of both α- and ß-CDs. In addition, the interaction between limaprost and the two CDs was reinforced by inclusion of different moieties of limaprost: α-CD predominantly included the alkyl ω-chain, whereas ß-CD included the five-membered ring. Thus, a stable ternary inclusion complex was formed that included limaprost, maintaining the amorphous state of the complex and dramatically stabilizing the drug under humid conditions.

The formation of an inclusion complex between a metabolite of ginsenoside, compound K and γ-cyclodextrin and its dissolution characteristics.

OBJECTIVES: 20S-protopanaxadiol 20-O-ß-D-glucopyranoside (compound K), a metabolite of ginsenoside, is only sparingly soluble in water. The aim of this study was to improve the low solubility, slow dissolution rate and low oral bioavailability of compound K by forming an inclusion complex with γ-cyclodextrin (γ-CyD), and to compare the results with those of ß-CyD complex. METHODS: The interactions of compound K with ß and γ-CyDs were studied by the solubility method and proton nuclear magnetic resonance spectroscopy. Solid forms of compound K/CyD complexes with different molar ratios were prepared by the kneading method, and the resulting complex was characterized by powder X-ray diffractometry. The dissolution rate of the complexes was measured by the rotary disk method. In-vivo absorption studies in rats were carried out, and the serum level of compound K, after its oral administration, was measured by a liquid chromatography-tandem mass spectrometry system. KEY FINDINGS: γ-CyD markedly improved the low solubility of compound K at lower CyD concentrations (<0.03 M), whereas the solubility was decreased at higher concentrations (>0.06 m). The enhancement in solubility by γ-CyD at a lower concentration was much higher than the corresponding values for ß-CyD. The apparent 1:1 stability constant (1.5 × 10(5) m(-1) ) for the γ-CyD complex was 18-fold larger than that (8.2 × 10(3) m(-1) ) of the ß-CyD complex. The dissolution rate of the 1:1 compound K/γ-CyD complex was faster than that for the 1:3 (guest : host) complex. These results suggest that the dissolution rate of the 1:1 complex, in which the drug is partially included, was faster than that of the 1:3 complex, in which the drug was completely included, due to the higher solubility and amorphous property of the former complex compared with the properties of the latter complex. The fast dissolution of the γ-CyD complex was reflected in the maximum plasma level (Cmax ) of the drug and the time (Tmax ) to reach the maximum plasma level after its oral administration to rats. CONCLUSIONS: The effect of γ-CyD on enhancing the solubility of compound K is much higher than that for the ß-CyD complex, and the dissolution rate of the guest when it is partially included in the γ-CyD is faster the corresponding value when it is completely included in the cavity.

Antioxidant and renoprotective activity of 2-hydroxypropyl-ß-cyclodextrin in nephrectomized rats.

OBJECTIVES: Oxidative stress is known to be involved in the pathogenesis of chronic renal failure (CRF). In this study, the effect of cyclodextrins (CDs) on oxidative stress and CRF was investigated using 5/6 nephrectomized rats as model animals. METHODS: CRF model rats were divided into five groups and treated for 8 weeks as follows: control, α-CD, ß-CD, γ-CD and 2-hydroxypropyl-ß-CD (HP-ß-CD). Blood was collected from the rats after 4 and 8 weeks for an analysis of renal function and oxidative stress tests were carried out. KEY FINDINGS: An oral administration of HP-ß-CD over an 8-week period resulted in a significant decrease in serum indoxyl sulphate, creatinine and urea nitrogen levels, compared with the other CDs. The ingestion of HP-ß-CD also resulted in an increase in antioxidant potential, compared with the other CDs. In in vitro studies, the interaction of HP-ß-CD with a uremic toxin, indole molecule, was much higher than that for the other CDs, as evidenced by Proton nuclear magnetic resonance ((1) H NMR) measurements. CONCLUSIONS: These results suggest that the ingestion of HP-ß-CD might result in a significant reduction in the levels of pro-oxidants in the gastrointestinal tract, such as uremic toxins, thereby inhibiting the subsequent development of oxidative stress in the systemic circulation.

Formation of the ternary inclusion complex of limaprost with α- and ß-cyclodextrins in aqueous solution.

The inclusion mode of Limaprost in the presence of α- and ß-cyclodextrins (CDs) was investigated to gain insight into the stabilization mechanism of Limaprost-alfadex upon the addition of ß-CD in the solid state. The inclusion sites of α- and ß-CDs were studied by NMR spectroscopic and kinetic methods. With the addition of α- and ß-CDs, displacements in (13)C chemical shifts of prostaglandin F2α (PGF2α) were observed in the ω-chain and the five-membered ring, respectively, of the drug. Similar shift changes were observed with the addition of both α- and ß-CDs. In two-dimensional (2D) (1)H-NMR spectra, intermolecular correlation peaks were observed between protons of PGF2α and protons of both α- and ß-CDs, suggesting that PGF2α interacts with α- and ß-CDs to form a ternary complex by including the ω-chain with the former CD and the five-membered ring with the latter. In kinetic studies in aqueous solution, Limaprost was degraded to 17S,20-dimethyl-trans-Δ(2)-PGA1 (11-deoxy-Δ(10)) and 17S,20-dimethyl-trans-Δ(2)-8-iso-PGE1 (8-iso). The addition of α-CD promoted the dehydration to 11-deoxy-Δ(10), while ß-CD promoted the isomerization to 8-iso, under these conditions. In the presence of both α- and ß-CDs, dehydration and isomerization were also accelerated, supporting the formation of the ternary Limaprost/α-CD/ß-CD complex.

Slow-release of famotidine from tablets consisting of chitosan/sulfobutyl ether ß-cyclodextrin composites.

An intermolecular complex formed from a 1:1 weight ratio of chitosan (CS, molecular weight 30 kDa) and sulfobutyl ether ß-cyclodextrin (SBE-ß-CyD, degree of substitution 7) was less soluble than either of the original components. The release of famotidine from tablets composed of a simple mixture of CS and SBE-ß-CyD is slower in media at pH 1.2 than at 6.8. Macroscopic observation of tablets and a kinetic analysis of release profiles suggested that, at pH 1.2, the drug was slowly released from the less-soluble CS/SBE-ß-CyD complex formed on the surface of the tablet immediately after exposure to water, accompanied by the dissolution of the interpolymer complex and, ultimately, the erosion and disintegration of the tablet. In the case of the medium at pH 6.8, the formation of a gel by CS was the cause of the slow release, especially for CS/SBE-ß-CyD tablets which were significantly gelated and both the diameter and thickness of the tablet had expanded. The in vitro slow releasing characteristic of the CS/SBE-ß-CyD tablet was reflected in the in vivo absorption of the drug after oral administration to rats. These results suggest that a simple mixing of CS and SBE-ß-CyD is potentially useful for the controlled release of a drug.

Preparation of hydrophilic C60(OH)10/2-hydroxypropyl-ß-cyclodextrin nanoparticles for the treatment of a liver injury induced by an overdose of acetaminophen.

Stable hydrophilic C60(OH)10 nanoparticles were prepared from 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and applied to the treatment of an acetaminophen overdose induced liver Injury. C60(OH)10 nanoparticles were produced by cogrinding α-CD, ß-CD, γ-CD and HP-ß-CD and characterized in terms of solubility, mean particle diameter, ζ-potential and long term dispersibility in water. Hydrophilic C60(OH)10 nanoparticles with particle sizes less than 50 nm were effectively produced by cogrinding HP-ß-CD with C60(OH)10 at a molar ratio of 1:3 (C60(OH)10:CD). The resulting C60(OH)10/HP-ß-CD nanoparticles were stable in water and showed no aggregation over a 1 month period. The C60(OH)10/CDs nanoparticles scavenged not only free radicals (DPPH and ABTS radicals) but also reactive oxygen species (O2(•-) and •OH). When C60(OH)10/HP-ß-CD nanoparticles were intraperitoneally administered to mice with a liver injury induced by an overdose of acetaminophen (APAP), the ALT and AST levels were markedly reduced to almost the same level as that for normal mice. Furthermore, the administration of the nanoparticles prolonged the survival rate of liver injured mice, while all of the mice that were treated with APAP died within 40 h. To reveal the mechanism responsible for liver protection by C60(OH)10 nanoparticles, GSH level, CYP2E1 expression and peroxynitrite formation in the liver were assessed. C60(OH)10/HP-ß-CD nanoparticles had no effect on CYP2E1 expression and GSH depletion, but suppressed the generation of peroxynitrite in the liver. The findings indicate that the protective effect of C60(OH)10/HP-ß-CD nanoparticles was due to the suppression of oxidative stress in mitochondria, as the result of scavenging ROS such as O2(•-), NO and peroxynitrite, which act as critical mediators in the liver injuries.

Effects of chitosan on oxidative stress and related factors in hemodialysis patients.

In recent world-wide studies, chitosans were tested as a dietary supplement for inhibiting the absorption of certain lipids and bile acids. We previously demonstrated the antioxidative and renoprotective potential of chitosan supplementation in chronic renal failure using 5/6 nephrectomized rats. In this study, we report the effects of chitosan on oxidative stress and related factors in hemodialysis patients. The ingestion of chitosan over a 12-week period resulted in a significant decrease in serum indoxyl sulfate and phosphate levels, compared with the levels prior to the start of the study. The ingestion of chitosan also resulted in a lowered ratio of oxidized to reduced albumin and a decrease in the level of advanced oxidized protein products. In in vitro studies, chitosan solutions were found to bind 38.5% of the indoxyl sulfate and 17.8% of the phosphate, respectively. Further, the oxidized albumin ratio was correlated with serum indoxyl sulfate levels in vivo. These results suggest that the ingestion of chitosan results in a significant reduction in the levels of pro-oxidants, which include uremic toxins, in the gastrointestinal tract, thereby inhibiting the subsequent development of oxidative stress in the systemic circulation. In addition, the long-term ingestion of chitosan has the potential for use in treating hyperphosphatemia in hemodialysis patients.

Preparation and antioxidant activity of PEGylated chitosans with different particle sizes.

The preparation of water-soluble chitosans such as polyethylene glycol (PEG)-grafted derivatives is essential for improving the biocompatibility and water solubility of these types of polysaccharides. In this study, chitosans (CS1; 22 kDa, CS2; 38 kDa, CS3; 52 kDa) with different molecular weights were modified with a succinyl ester derivative of monomethoxypolyethylene glycol (mPEG-COONSu; 2 kDa), and the properties of the resulting conjugates (mPEG-CS1, mPEG-CS2, mPEG-CS3) were investigated. The antioxidant properties of these mPEG-CSs were examined using (1) N-centered radicals derived from 1,1'-diphenyl-2-picrylhydrazyl (DPPH), (2) reducing power, based on their ability to reduce Cu2+ and (3) hydroxyl radicals via the use of ESR spectrometry. The order of their effectiveness was mPEG-CS1>mPEG-CS2>mPEG-CS3, i.e. mPEG-CS1 with a low particle size had the highest scavenging activity of the mPEG-CSs tested. In an in vivo study, we examined the effect of mPEG-CS1 on liver injury, caused by injecting mice with Concanavalin A (Con A). The livers of mice that were treated with mPEG-CS1 were protected from Con A-induced injury. Further, pre-treatment with mPEG-CS1 dramatically reduced the mortality associated with Con A-induced mortality. These findings suggest that mPEG-CS1 could be potentially useful in the treatment of immune-mediated liver injury.

Stabilizing effect of ß-cyclodextrin on Limaprost, a PGE1 derivative, in Limaprost alfadex tablets (Opalmon) in highly humid conditions.

Stabilization against humidity of Limaprost (a prostaglandin E1 derivative), which is currently marketed as Opalmon, was undertaken using ß-cyclodextrin (ß-CD). Aqueous solutions of Limaprost alfadex/dextran 40 were lyophilized with and without ß-CD. Limaprost alfadex lyophilized with ß-CD was more chemically stable in humid conditions than that without ß-CD. Moreover, the addition of ß-CD as an excipient to tablets of these lyophilized composites remarkably improved the stability of Limaprost, and Limaprost in this moisture-resistant formulation was chemically stable for 19 weeks at 30°C, 75% relative humidity (R.H.). Chemical analysis of Limaprost and its degradation products indicated that degradation proceeded in the inclusion form (i.e., within the CD cavity). Solid (2)H-NMR spectroscopic studies showed that ß-CD constrained the molecular mobility of water in the solid state. These results suggested that the stabilization of Limaprost by ß-CD was at least partly due to the restricted molecular mobility of water, which acted as a catalytic species for the degradation, and also to the protection of the five-membered ring of Limaprost from water catalytic dehydration through inclusion complex formation with ß-CD.

Cyclodextrins improve oral absorption of a novel factor Xa inhibitor by interfering with interaction between the drug and bile acids in rats.

OBJECTIVES: Poor oral absorption of a factor Xa inhibitor, DX-9065, is partly due to the interaction with bile acids in the gastrointestinal tract. The aim of this study is to improve the oral bioavailability of DX-9065 by cyclodextrins (CyDs) capable of interfering with such interaction. METHODS: The abilities of the CyDs to interfere with the interaction between DX-9065 and sodium chenodeoxycholate were evaluated using equilibrium dialysis. The interaction between DX-9065 and the CyDs was studied spectroscopically. Effects of the CyDs on the oral absorption of DX-9065 were examined in rats. KEY FINDINGS: Hydroxypropyl-ß-CyD and γ-CyD were effective in interfering with the interaction between DX-9065 and sodium chenodeoxycholate as a representative bile acid. Spectroscopic studies revealed that DX-9065 was included into the CyD cavity to form inclusion complexes in an acidic medium. With dissociation of the carboxyl group of DX-9065 in a neutral medium, the stability of the complexes was decreased to such an extent that DX-9065 in the cavity is replaced with co-existing bile acids. The average area under the plasma concentration-time curve value after oral administration of DX-9065 with hydroxypropyl-ß-CyD was 2.5 times higher than that of DX-9065 alone with a statistical difference in rats. CONCLUSIONS: We suggest that the CyDs are useful in designing oral formulations of DX-9065 with an improved bioavailability.