Salvia miltiorrhiza Induces Tonic Contraction of the Lower Esophageal Sphincter in Rats via Activation of Extracellular Ca2+ Influx.

Up to 40% of patients with gastroesophageal reflux disease (GERD) suffer from proton pump inhibitor refractory GERD but clinically the medications to strengthen the lower esophageal sphincter (LES) to avoid irritating reflux are few in number. This study aimed to examine whether Salvia miltiorrhiza (SM) extracts induce tonic contraction of rat LES ex vivo and elucidate the underlying mechanisms. To investigate the mechanism underlying the SM extract-induced contractile effects, rats were pretreated with atropine (a muscarinic receptor antagonist), tetrodotoxin (a sodium channel blocker), nifedipine (a calcium channel blocker), and Ca(2+)-free Krebs-Henseleit solution with ethylene glycol tetraacetic acid (EGTA), followed by administration of cumulative dosages of SM extracts. SM extracts induced dose-related tonic contraction of the LES, which was unaffected by tetrodotoxin, atropine, or nifedipine. However, the SM extract-induced LES contraction was significantly inhibited by Ca(2+)-free Krebs-Henseleit solution with EGTA. Next, SM extracts significantly induce extracellular Ca(2+) entry into primary LES cells in addition to intracellular Ca(2+) release and in a dose-response manner. Confocal fluorescence microscopy showed that the SM extracts consistently induced significant extracellular Ca(2+) influx into primary LES cells in a time-dependent manner. In conclusion, SM extracts could induce tonic contraction of LES mainly through the extracellular Ca(2+) influx pathway.

Preparation, physicochemical characterization, and antioxidant effects of quercetin nanoparticles.

The purpose of this study was to develop quercetin-loaded nanoparticles (QUEN) by a nanoprecipitation technique with Eudragit E (EE) and polyvinyl alcohol (PVA) as carriers, and to evaluate the antioxidant effects of quercetin (QU) and of its nanoparticles. The novel QUEN systems were characterized by particle size and morphology, yield and encapsulation efficiency, differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), (1)H nuclear magnetic resonance ((1)H NMR), and dissolution study. It was observed that the weight ratio of QU:EE:PVA at 1:10:10 carried a particle size of <85 nm, a particle distribution with polydispersity index <0.3, and its yield and encapsulation efficiency were over 99%. The results from XRD and DSC of the QUEN showed that the crystal of the drug might be converted to an amorphous state. The FT-IR and (1)H NMR demonstrated that QU formed intermolecular hydrogen bonding with carriers. The release of the drug from the QUEN was 74-fold higher compared with the pure drug. In addition, the antioxidant activity of the QUEN was more effective than pure QU on DPPH scavenging, anti-superoxide formation, superoxide anion scavenging, and anti-lipid peroxidation.

An investigation of acetylcholine released in skeletal muscle and protein unbound drug released in blood based on the pyridostigmine bromide (pretreatment drug) sustained-release pellets by microdialysis technique in the rabbit model.

Pyridostigmine bromide (PB) is a reversible acetylcholinesterase inhibitor that has been used as a pretreatment drug for "Soman" nerve gas poisoning in combat to increase survival. The once-daily PB-sustained-release (SR) pellets were developed by extrusion-spheronization and fluid-bed methods in our laboratory, which was followed by zero-order release mechanism. The results showed that the released concentration of acetylcholine (ACh) in skeletal muscle and the released concentration of protein unbound drug in blood were determined by microdialysis technique to have significant differences (P<0.05) among the three dosage forms (IV injection, commercial IR tablets and the PB-SR pellet). The released concentrations of ACh and protein unbound drug for PB-SR pellets were slower than IV injection and commercial IR tablets; this phenomenon indicating that the retention period of drug efficacy in vivo for PB-SR pellet was longer than the others, that is to say, the PB-SR pellets provided with SR effect in vivo as well. We believe that once-daily administered PB-SR pellets would improve limitations of post-exposure antidotes, decrease the frequency of administration and enhance the retention period of drug efficacy in vivo for personnel exposed to contamination situations in wars or terrorist attacks in the future.

Liquid chromatographic method with amperometric detection to determine acteoside in rat blood and brain microdialysates and its application to pharmacokinetic study.

A simple and sensitive liquid chromatography with amperometric detection was developed for the first time to monitor the protein-unbound acteoside in the rat blood and brain microdialysate by microdialysis technique. Microdialysis samples without further cleanup procedures were directly injected into the HPLC and separated using a reversed-phase C18 column (150 mmx2 mm, i.d. 5 microm) maintained at ambient temperature and a mobile phase comprised of acetonitrile-50 mM monosodium phosphate (pH 2.8) (17:83, v/v) with a flow rate of 0.2 mL/min. Based on the experimental voltamogram, the applied potential was set at +0.9 V oxidative mode. The concentration-response relationship was linear (r2>0.99) over a concentration range of 5-500 ng/mL; method precision and accuracy fell within predefined limits (less than 20%). The developed method was applied to assess the pharmacokinetics of acteoside, and the results suggested that acteoside was fitted better by the two-compartmental model following a single intravenous injection of acteoside. Acteoside was unable to be detected in the brain dialysate. The distribution and elimination half-lives of unbound acteoside in the blood were 5 and 28 min, respectively, which suggested the rapid distribution of acteoside.

Microencapsulation of extract containing shikonin using gelatin-acacia coacervation method: a formaldehyde-free approach.

The application of microcapsule for pharmaceutical dosage form for various drugs has received considerable attention in recent years due to its multiple advantages. The most frequently used crosslinking agent formaldehyde in the gelatin-acacia microencapsulation process was altered by glycerol in this study. The effect of various parameters such as the concentration of surfactant, concentration of gelatin and continuous phase pH condition on the microcapsule particle size distribution was experimentally investigated. It was shown that the optimum concentration for surfactant/oil ratio is 1/10 and gelatin/oil ratio is 1/5 in the pH condition of approximately 4-6 for the coacervation process. Results obtained from microscopy observation revealed that one core microcapsule prepared by 6% glycerol was no different from formaldehyde. Hence, glycerol was demonstrated to be a good potential non-toxic crosslinking material for the applications of encapsulated extract containing shikonin.

Measurement of unbound ranitidine in blood and bile of anesthetized rats using microdialysis coupled to liquid chromatography and its pharmacokinetic application.

To investigate the pharmacokinetics of unbound ranitidine in rat blood and bile, multiple microdialysis probes coupled to a liquid chromatographic system were developed. This study design was parallel in the following groups: the control-group of six rats received ranitidine alone (10 and 30 mg/kg, i.v.), the treated-group rats were co-administered with ranitidine and cyclosporine (P-glycoprotein (P-gp) inhibitor) or quinidine (both organic cation transport (OCT) and P-gp inhibitors) in six individual rats. Microdialysis probes were inserted into the jugular vein and the bile duct for blood and bile fluids sampling, respectively. Ranitidine in the dialysate was separated by a reversed-phase C18 column (Zorbax, 150 mm x 4.6 mm i.d.; 5 microm) maintained at ambient temperature. Samples were eluted with a mobile phase containing acetonitrile-methanol-tetrahydrofuran-20 mM K2HPO4 (pH 7.0) (24:20:10:946, v/v), and the flow rate of the mobile phase was 1 ml/min. The optimal UV detection for ranitidine was set at wavelength 315 nm. Between 20 and 30 min after drug administration (10 or 30mg/kg), the ranitidine reached the maximum concentration in the bile. The bile-to-blood distribution ratio (AUC(bile)/AUC(blood)) was 9.8 +/- 1.9 and 13.9 +/- 3.8 at the dosages of 10 and 30 mg/kg, respectively. These studies indicate that ranitidine undergoes hepatobiliary excretion which against concentration gradient from bile-to-blood. In addition, the AUC of ranitidine in bile decreased in the treatment of cyclosporine or quinidine, which suggests that the hepatobiliary excretion of ranitidine was partially regulated by P-glycoprotein or organic cation transporter.

Mechanism of bombesin-induced tonic contraction of the porcine lower esophageal sphincter.

Gastroesophageal reflux disease (GERD) is a disorder that is related to an incompetent lower esophageal sphincter (LES). Previous studies showed that bombesin could increase LES pressure in humans and opossums. The aim of the present study was to characterize the effects of bombesin on porcine LES contraction. We used the selective agonists, neuromedin B (NMB), gastrin-releasing peptide (GRP), and [D-Tyr(6),Apa-4Cl(11),Phe(13),Nle(14)]bombesin-(6-14) (DTACPN-BN), as well as receptor antagonists of bombesin receptor subtype 2 (BB2), and 3 (BB3) for ex vivo contraction studies. Atropine, nifedipine, tetrodotoxin, and ω-conotoxin GVIA were used to explore the agonist-induced LES contraction mechanism. Reverse transcription polymerase chain reaction and immunohistochemistry were applied to detect bombesin receptor expression. Our results indicate that GRP and DTACPN-BN, but not NMB, induced tonic contractions of the porcine LES in a dose-dependent manner, and the contractions were inhibited with selective BB2 and BB3 antagonists. The GRP-induced contraction is mainly caused by L-type Ca(2+) channel-mediated Ca(2+) influx. However, DTACPN-BN-induced contractions are associated with neuronal conduction. RT-PCR and immunohistochemistry revealed that BB2 and BB3 were expressed in the porcine LES. Bombesin-induced tonic contraction of the LES is mediated through BB2 and BB3. Bombesin, BB2, and BB3 agonists might have the potential to treat GERD.

Identification and determination of geniposide contained in Gardenia jasminoides and in two preparations of mixed traditional Chinese medicines.

A high-performance liquid chromatographic method was applied to the determination of the geniposide concentration in Gardenia fruit and preparations of traditional Chinese medicine using a mobile phase of acetonitrile-methanol-5 mM monosodium phosphate (pH 4.6) (5:15:80, v/v/v). Intra-assay and inter-assay accuracy and precision of the analyses were < or = 10% in the range of 0.1 through 50 microg/ml. The presence of geniposide in the medicinal herb and its preparations was ascertained by retention time, spiking with an authentic standard, change of detection wavelength and change of the composition of the mobile phase. The concentration of geniposide in the fruit of Gardenia jasminoides Ellis var. grandiflora Nakai is higher than that in Gardenia jasminoides Ellis. The concentration of geniposide in the traditional Chinese herbal medicine preparations, Huang-Lian-Jiee-Dwu-Tang (66.27 +/- 1.98 mg/g) and In-Chern-Hau-Tang (68.54 +/- 2.62 mg/g) was less than in the herb Gardenia jasminoides Ellis (73.44 +/- 2.62 mg/g) itself.

Preparation and characterization of gelatin-based mucoadhesive nanocomposites as intravesical gene delivery scaffolds.

This study aimed to develop optimal gelatin-based mucoadhesive nanocomposites as scaffolds for intravesical gene delivery to the urothelium. Hydrogels were prepared by chemically crosslinking gelatin A or B with glutaraldehyde. Physicochemical and delivery properties including hydration ratio, viscosity, size, yield, thermosensitivity, and enzymatic degradation were studied, and scanning electron microscopy (SEM) was carried out. The optimal hydrogels (H), composed of 15% gelatin A175, displayed an 81.5% yield rate, 87.1% hydration ratio, 42.9 Pa·s viscosity, and 125.8 nm particle size. The crosslinking density of the hydrogels was determined by performing pronase degradation and ninhydrin assays. In vitro lentivirus (LV) release studies involving p24 capsid protein analysis in 293T cells revealed that hydrogels containing lentivirus (H-LV) had a higher cumulative release than that observed for LV alone (3.7-, 2.3-, and 2.3-fold at days 1, 3, and 5, resp.). Lentivirus from lentivector constructed green fluorescent protein (GFP) was then entrapped in hydrogels (H-LV-GFP). H-LV-GFP showed enhanced gene delivery in AY-27 cells in vitro and to rat urothelium by intravesical instillation in vivo. Cystometrogram showed mucoadhesive H-LV reduced peak micturition and threshold pressure and increased bladder compliance. In this study, we successfully developed first optimal gelatin-based mucoadhesive nanocomposites as intravesical gene delivery scaffolds.

The association between circulating endothelial progenitor cells and outcome in different subtypes of acute ischemic stroke.

OBJECTIVES: This study evaluated the relationship between serial changes in circulating endothelial progenitor cells (EPCs) and outcomes in patients with different subtypes of acute ischemic stroke (AIS). METHODS: This prospective cohort study evaluated 65 patients with AIS, including 45 with small-vessel and 20 with large-vessel diseases. The circulating level of EPCs (CD133(+)/CD34(+) and KDR(+)/CD34(+) cells) was determined at different time points (within 48h and on Days 7 and 30 post-stroke). For comparison, the EPC levels of 65 age- and sex-matched controls were also evaluated. RESULTS: The levels of CD133(+)/CD34(+) and KDR(+)/CD34(+) EPCs were significantly lower in the AIS group than in the control group (p<0.05). There were fewer CD133(+)/CD34(+) EPCs in the large-vessel disease group than in the small-vessel disease group on Day 1 post-stroke (p<0.05). After adjusting for covariance using stepwise logistic regression, only stroke subtype (OR: 30.2, 95% CI: 5.3-171.4; p<0.001) and KDR(+)/CD34(+) on admission (OR: 0.188, 95% CI: 0.04-0.86; p=0.031) were independently associated with 6-month outcome. CONCLUSIONS: The number of circulating EPCs is significantly lower in patients with large-vessel disease than in those with small-vessel disease. Fewer number of EPCs on admission is an independent risk factor for poor 6-month outcome in patients with AIS.

Optimization of rate-controlled 17beta-estradiol nanoparticles for cerebral ischemia therapy.

The objective of this study was to prepare and evaluate rate-controlled 17beta-estradiol nanoparticles (E2-NPs), and then optimize them by central composite design (CCD) using a response surface methodology (RSM). The E2-NPs were designed for cerebral ischemia therapy and prepared by oil-in-water (o/w) emulsion by mixing E2 and phosphatidylcholine, cross-linking of the bovine serum albumin (BSA) wall material with glutaraldehyde, and subsequently creating a biodegradable coating shell with L-arginine. In two-factor, five-level CCD, the independent variables were the pH value of the aqueous phase (X1) and the amount of glutaraldehyde (X2). The optimal formulation of the E2-NPs was developed from the response equations of each fitted model. The optimal E2-NPs particle size was 92.4 +/- 1.4 nm, and its cumulative release in 4.0 h (therapeutic window for stroke) was 71.17 +/- 0.24%, with a zero-order release model of 24 h. The preparation and testing of the optimal formulation showed a good correlation between the predicted and observed values. In addition, a brain microdialysis study demonstrated that the E2-NPs had the ability to penetrate the blood-brain barrier and clearly increase and maintain the drug concentration in the brain over 12 h. Furthermore, the E2-NPs reduced brain infarct size in rats with middle cerebral artery occlusion (MCAO)-induced stroke. These results suggest that rate-controlled E2-NPs increase the efficacy of E2 for ischemic stroke therapy.

Elevating bioavailability of curcumin via encapsulation with a novel formulation of artificial oil bodies.

Utilization of curcumin has been limited due to its poor oral bioavailability. Oral bioavailability of hydrophobic compounds might be elevated via encapsulation in artificial seed oil bodies. This study aimed to improve oral bioavailability of curcumin via this encapsulation. Unfortunately, curcumin was indissoluble in various seed oils. A mixed dissolvent formula was used to dissolve curcumin, and the admixture was successfully encapsulated in artificial oil bodies stabilized by recombinant sesame caleosin. The artificial oil bodies of relatively small sizes (150 nm) were stably solidified in the forms of powder and tablet. Oral bioavailability of curcumin with or without encapsulation in artificial oil bodies was assessed in Sprague-Dawley male rats. The results showed that encapsulation of curcumin significantly elevated its bioavailability and provided the highest maximum whole blood concentration (Cmax), 37 ± 28 ng/mL, in the experimental animals 45 ± 17 min (t(max)) after oral administration. Relative bioavailability calculated on the basis of the area under the plasma concentration-time curve (AUC) was increased by 47.7 times when curcumin was encapsulated in the artificial oil bodies. This novel formulation of artificial oil bodies seems to possess great potential to encapsulate hydrophobic drugs for oral administration.

Discovery, synthetic methodology, and biological evaluation for antiphotoaging activity of bicyclic[1,2,3]triazoles: in vitro and in vivo studies.

Novel bicyclic[1,2,3]triazoles (4, 7, 11, 15) have been synthesized using a one-pot metal free strategy with high structural diversity as photoprotective agents, and their effect on UVA-induced senescence in human dermal fibroblast cells (FB) and the associated mechanism are delineated. 11d plus UVA can induce a decrease in reactive oxygen species (ROS) production and senescence-associated ß-galactosidase (SA-ß-gal) activity but an increase in adenosine triphosphate (ATP) synthesis and mitochondrial membrane potential (ΔΨmt). The mRNA levels of six senescence-associated genes, matrix metalloproteinase-1 (MMP-1), was decreased, while elastin, procollagen I type I, fibronectin, COL1α1, and tissue inhibitor of metalloproteinase-1 (TIMP-1) were increased. 11d plus UVA also decreased MMP-1 and increased TIMP-1 protein levels. Additionally, the thickness of the murine dorsal skin and epidermis, by UVA, was decreased by topical 11d treatment. Our results indicate that bicyclic[1,2,3]triazoles protect UVA-induced senescence-like characteristics in FB cells, which may provide potential prevention against photoaging.

Salvia miltiorrhiza causes tonic contraction in rat ileum through Ca²âº-calmodulin pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Danshen, root of Salvia miltiorrhiza (SM), has been traditionally used in Chinese medicine for the treatment of heart, abdomen, gurgling in the intestines, and relieving fullness. However, the effects of SM on intestine have rarely been done to date. AIM OF THE STUDY: To investigate the contraction effect of SM on isolated rat ileum and its mechanisms involved. MATERIALS AND METHODS: The isometric contractions of ileum segments were investigated in organ baths for spontaneous activity and response to ethanolic extracts of SM. To determine the contraction mechanism caused by SM extracts, atropine (a muscarinic receptor antagonist), tetrodotoxin (TTX, a sodium channel blocker), nifedipine (a calcium channel blocker), Ca(2+) free Krebs solution with EGTA, or trifluoperazine (TFP, a calmodulin blocker) was administered and its response to cumulative dosages of SM extracts were examined. The effect of SM extracts on Ca(2+) signaling in the intestinal epithelial cell-6 (IEC-6) was examined using fura-2 as a Ca(2+) indicator. RESULTS: SM extracts caused dose-dependent tonic contraction on rat ileum in ex vivo organ bath studies. The contraction induced by SM extracts was not inhibited by atropine, TTX, nifedipine, or in Ca(2+) free solution. However, the ileal contractions induced by SM extracts were significantly inhibited by TFP in a dose-dependent manner. In IEC-6 cells, the SM extracts induced extracellular Ca(2+) entry and massive intracellular Ca(2+) release in Ca(2+)-contained medium, and induced intracellular Ca(2+) release in Ca(2+)-free medium. CONCLUSION: These results demonstrate that SM extracts cause ileal contraction through the Ca(2+)-calmodulin pathway.

Preparation, characterization and cytotoxicity evaluation of tanshinone IIA nanoemulsions.

Tanshinone IIA (TA) is a major active component of Danshen (Salvia miltiorrhiza bunge), a well-known traditional Chinese medicine. In this paper, we describe an optimal method for preparing TA nanoemulsions (TA-NEs) to solve the problems of TA's poor solubility in water and insufficient dissolution rate. Optimization of the method for preparing nanoemulsions of lipid soluble TA by emulsification/high pressure homogenization was carried out with a 2(3) factorial design, using Tween 80, lecithin and water content as independent variables. The particle size, entrapment efficiency and polydispersity index of eight formulations were then evaluated. Two optimal formulations, TA-NE-F2 and TA-NE-F4, were developed and both exhibited markedly enhanced in vitro release ability, as compared to TA. However, only TA-NE-F4 remained stable for over 3 months. TA-NE-F4 particles were spherical and intact, with a mean particle size of 95.6 nm and a high entrapment efficiency of 99.3%, TA-NE-F4 showed a fast dissolution rate of 80% in 10 min and 100% in 20 min. The cytotoxicity of TA-NE-F4 against T24 human bladder cancer cells was 103.4-fold greater than TA alone in both a time- and a dose-dependent manner. Overall, we describe a feasible method for preparing TA-NEs that exhibit potent cytotoxicity.

Preliminary study of a traditional Chinese medicine formula in systemic lupus erythematosus patients to taper steroid dose and prevent disease flare-up.

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease. Prolonged complete remission is rare. Most patients with SLE need long-term treatment with glucocorticoid and immunomodulators. However, side effects because of the above medications are common. We evaluated the effect of adding-on Dan-Chi-Liu-Wei combination (DCLWC) on SLE patients with conventional therapy in tapering steroid and preventing disease flare-up. This was a double-blind and randomized controlled trial. Sixty-six SLE patients were recruited into this study and 53 patients who fulfilled the 1997 revised criteria for the classification of SLE with an SLE disease activity index (SLEDAI) score of 2-12 and a steroid (measured with prednisolone) daily dose of less than 20mg/d were enrolled. The patients were randomized into either an experimental or control group. We checked the urine analysis, hemogram, liver function, renal function, C3, C4, erythrocyte sedimentation rate, and anti-dsDNA, evaluated the SLEDAI score, and recorded the steroid dose at 0 months, 3 months, and 6 months, respectively. After 6 months of study, the C4 and blood urea nitrogen level revealed a statistically significant difference in either group. There was a tendency toward a decreased SLEDAI score in the experimental group (p=0.083) but not in the control group (p=0.867). The steroid dose was not statistically significant in either group. Renal function and liver function revealed no statistically significant statistics changes in either group. Adding-on DCLWC to conventional therapy for the treatment of SLE was safe and might have a borderline effect in decreasing disease activity, but it was not possible to taper the dosage of steroid after 6 months of clinical trial. Therefore, a long-term follow-up and a large-scale study are necessary to confirm the effect of DCLWC.

Optimization of epirubicin nanoparticles using experimental design for enhanced intravesical drug delivery.

The aim of this study was to develop poly(ethyl-2-cyanoacrylate) (PECA) epirubicin-loaded nanoparticles (EPI-NP). A 2(3) factorial design was adopted with the type of surfactant, surfactant concentration and the pH of the polymerization medium as independent variables. The particle size, entrapment efficacy and polydispersity index of eight formulations were then evaluated. Two optimal EPI-NP formulations, 2% Tween 80 EPI-NP (TW80 EPI-NP) and 0.5% pluronic F68 EPI-NP (F68 EPI-NP) at pH 2.5 were developed. The sizes of TW80 EPI-NP and F68 EPI-NP at maximum intensity were 90 and 220 nm, respectively. Both TW80 EPI-NP and F68 EPI-NP showed potent cytotoxicity against human bladder cancer T24 and RT4 cells, compared with aqueous solutions of epirubicin (EPI-AQ). The penetration and accumulation of EPI-NPs in pig urothelium were studied by tissue concentration-depth profiles and fluorescence microscopy. The cumulative amounts of epirubicin following EPI-AQ, TW80 EPI-NP and F68 EPI-NP treatments were 842.48+/-24.66, 1314.66+/-33.07 and 595.21+/-24.16 microg, respectively. The current study showed the successful development of urothelium adhesive and penetrative PECA EPI-NPs. This has potential for the in vivo application of epirubicin-loaded nanoparticles for intravesical instillation in bladder cancer therapy.

Analysis of brain distribution and biliary excretion of a nutrient supplement, gastrodin, in rat.

Gastrodin is a bioactive constituent of rhizome in Gastrodia elata Blume (Orchidaceae) The aim of this study is to develop a rapid and sensitive liquid chromatographic method coupled to microdialysis sampling system to measure the unbound of gastrodin in rat blood, brain and bile. Microdialysis probes were simultaneously inserted into the jugular vein, brain striatum and bile duct of each anesthetized rat for sampling after the administration of gastrodin (100 or 300 mg kg(-1)) through the femoral vein. Separation of unbound gastrodin from various biological fluids was applied to an RP-select B column (250 mm x 4.6 mm i.d., 5 microm). The mobile phase consisted of acetonitrile-50 mM potassium dihydrogen phosphate buffer-triethylamine (5:95:0.1, v/v/v, adjusted to pH 2.5 with orthophosphoric acid) with a flow rate of 1 mL min(-1). The UV detector wavelength was set at 221 nm. Fifteen minutes after the administration, the gastrodin reached the peak concentration in brain and bile. In addition, the results indicate that gastrodin penetrates the blood-brain barrier (BBB) and goes through hepatobiliary excretion.

Comparison of the solubility and dissolution rate between gliclazide solid complex and its nanospheres.

The solid complex of gliclazide and beta-cyclodextrin was prepared by neutralization method and the precipitation solvent evaporation method was used to prepare gliclazide nanospheres. Fourier-transform infrared spectroscopy and differential scanning calorimetry were used to examine whether gliclazide solid complex and gliclazide nanospheres were successfully formed in this study. The dissolution rate of gliclazide from its nanospheres was faster than its solid complex and pure drug. The morphology of particles for nanospheres showed no crystal character of gliclazide. In summary, the results indicate that nanotechnology provides better effects in solubility and dissolution rate of gliclazide than neutralization method.

Formulation design of a highly hygroscopic drug (pyridostigmine bromide) for its hygroscopic character improvement and investigation of in vitro/in vivo dissolution properties.

Pyridostigmine bromide (PB) sustained-release (SR) pellets were developed by extrusion-spheronization and fluid-bed methods using Taguchi experimental and 2(3) full factorial design. In vitro studies, the 2(3) full factorial design was utilized to search for the optimal SR pellets with specific release rate at different time intervals (release percent of 2, 6, 12, and 24 hr were 6.24, 33.48, 75.18, and 95.26%, respectively) which followed a zero-order mechanism (n=0.93). The results of moisture absorption by Karl Fischer has shown the optimum SR pellets at 25 degrees C/60% RH, 30 degrees C/65% RH, and 40 degrees C/75% RH chambers from 1 hr-4 weeks, attributing that the moisture absorption was not significantly increased. In the in vivo study, the results of the bioavailability data showed the Tmax (from 0.65+/-0.082 hr-4.82+/-2.12 hr) and AUC0-30 hr (from 734.88+/-230.68 ng/mL.hr-1454.86+/-319.28 ng/mL.hr) were prolonged and increased, as well as Cmax (from 251.87+/-27.51 ng/mL-115.08+/-14.87 ng/mL) was decreased for optimum SR-PB pellets when compared with commercial immediate-release (IR) tablets. Furthermore, a good linear regression relationship (r=0.9943) was observed between the fraction dissolution and fraction absorption for the optimum SR pellets. In this study, the formulation design not only improved the hygroscopic character of PB but also achieved the SR effect.