Dexibuprofen Research Articles

Development of dexibuprofen loaded nano transfersomal gel with enhanced biopharmaceutical performance in complete Freund's adjuvant induced arthritis model

The purpose of this study was to enhance the biopharmaceutical performance of Dexibuprofen (DXI) using transfersomal gel (DXI-TG) as drug delivery system. DXI loaded transfersomes (DXI-T) were prepared via thin film technique, characterized for particle size, polydispersity index, zeta potential, particle morphology and entrapment efficiency. The DXI-T was further incorporated into 2 % (w/v) chitosan gel to get the final dosage form DXI-TG, which was characterized for homogeneity, pH, spread-ability and rheological properties. In vitro release, ex vivo permeation and in vivo studies were also conducted along with stability study of the optimized formulation. DXI-T showed excellent vesicle properties including, size distribution (235.1 ± 4.66 nm), poly dispersity index (0.184 ± 0.001), zeta potential (−10.5 ± 0.23 mV) and entrapment efficiency (82.9 ± 1.07 %). TEM analysis exhibited spherical morphology and uniformly distributed nanoparticles, whereas FTIR showed no bond anomalies. DXI-TG showed suitable gel properties with a viscosity of 11310 ± 20 cP, pH 5.2 ± 0.3, good homogeneity, non-Newtonian flow behavior, good spread-ability (298 ± 7.63 %) and high drug content (97.01 ± 3.1 %). in vitro release studies demonstrated that DXI-TG has significantly controlled the release of DXI when compared with DXI-T, DXI-G and DXI-Suspension at pH 5.5 and 7.4. Similarly, ex vivo permeation analysis showed meaningfully increased permeation of DXI-T followed by DXI-TG when compared with test formulations. Like normal control group, skin irritation studies showed no erythema and edema in DXI-TG treated group. Additionally, DXI-TG demonstrated a significantly enhanced bioavailability (5-fold) when compared with DXI-Suspension and DXI-G. Furthermore, DXI-TG showed significantly enhanced therapeutic effect against acute arthritis model when compared with DXI-Suspension and DXI-G. Besides, no signs of evident toxicity on major body organs was observed in DXI-TG treated animal group. Also, the DXI-TG was found stable for a period of 6 months. It can be concluded that transfersomal gel may be a suitable carrier for DXI with enhanced bioavailability, improved therapeutic efficacy and no evident toxicity as exhibited in this study.

Novel customized age-dependent corneal membranes and interactions with biodegradable nanoparticles loaded with dexibuprofen

Ocular inflammation is one of the most prevalent diseases in ophthalmology and it is currently treated using eye drops of nonsteroidal antiinflammatory drugs such as dexibuprofen (DXI). However, their bioavailability is low and therefore, PLGA nanoparticles constitute a suitable approach to be administered as eyedrops. Therefore, DXI has been encapsulated into PLGA nanoparticles (DXI-NPs). Although the eye, and specifically the cornea, suffers from age-related changes in its composition, current medications are not focused on these variations. Therefore, to elucidate the interaction mechanism of DXI-NPs with the cornea in relation with age, two different corneal membrane models have been developed (corresponding to adult and elder population) using lipid monolayers, large and giant unilamellar vesicles. Interactions of both DXI and DXI-NPs were studied with these models by means of Langmuir balance technique, dipole potential, anisotropy and confocal microscopy. In addition, fluorescently labelled nanoparticles were administered to mice in order to corroborate these data obtained in vitro. It was observed that DXI-NPs interact with lipid membranes through an adhesion process, mainly in the rigid regions and afterwards DXI-NPs are internalized by a wrapping process. Furthermore, differences on the dipole potential caused by DXI-NPs in each corneal membrane have been obtained due to the increase of membrane rigidity on the ECMM. Additionally, it can be confirmed that DXI-NPs adhere to Lo phase and also inside the lipid membrane. Finally, in vitro and in vivo results corroborate that DXI-NPs are adhered to the more ordered phase. Finally, differences between interactions of DXI-NPs with the elder and adult corneal tissue were observed.

Statistically designed dexibuprofen loaded solid lipid nanoparticles for enhanced oral bioavailability

Dexibuprofen (DBPN), a non-steroidal anti-inflammatory drug (NSAID), exhibit its action by inhibiting COX enzymes. It belongs to BCS class Ⅱ drugs, owing to its poor dissolution and reduced oral bioavailability. Herein, solid lipid nanoparticles (SLNs) were prepared by modified microemulsion method followed by their optimization via Design-Expert® (version 12). The optimized formulation was evaluated using various techniques including, Transmission electron microscopy (TEM), Fourier transform infrared spectrophotometer (FTIR), Powder x-ray diffractometer (PXRD) and Dynamic scanning calorimeter (DSC). In-vitro release and pharmacokinetic studies of DBPN-SLNs were executed and compared with drug suspension. A 12-weeks stability study was performed at 4 °C and 40 °C. Optimized formulation has spherical morphology including particle size (PS) of 213.8 nm, polydispersity index (PDI) of 0.201, zeta potential (ZP) of −33.6 mV and %EE of 92%. FTIR analysis showed no chemical interaction of the constituents of SLNs, whereas XRD and DSC respectively demonstrated the conversion of crystalline drug to amorphous and thermal behavior of the optimized formulation. In-vitro dissolution data indicated that SLNs has momentously retarded the drug release at various pH level when compared with drug suspension. Pharmacokinetic study revealed a significantly enhanced (9-fold) oral bioavailability of DBPN-SLNs than DBPN suspension. Moreover, DBPN-SLNs were stable for at-least 12 weeks. Hence, it can be concluded that incorporation of DBPN into SLNs produce sustained release behavior with improved bioavailability.

Novel Strategies against Cancer: Dexibuprofen-Loaded Nanostructured Lipid Carriers.

The aim of this work was to design innovative nanostructured lipid carriers (NLCs) for the delivery of dexibuprofen (DXI) as an antiproliferative therapy against tumoral processes, and overcome its side effects. DXI-NLC samples were prepared with beeswax, Miglyol 812 and Tween 80 using high-pressure homogenization. A two-level factorial design 24 was applied to optimize the formulation, and physicochemical properties such as particle size, zeta potential, polydispersity index and entrapment efficiency were measured. Optimized parameters of DXI-NLCs exhibited a mean particle size of 152.3 nm, a polydispersity index below 0.2, and high DXI entrapment efficiency (higher than 99%). Moreover, DXI-NLCs provided a prolonged drug release, slower than the free DXI. DXI-NLCs were stable for 2 months and their morphology revealed that they possess a spherical shape. In vitro cytotoxicity and anticancer potential studies were performed towards prostate (PC-3) and breast (MDA-MB-468) cancer cell lines. The highest activity of DXI-NLCs was observed towards breast cancer cells, which were effectively inhibited at 3.4 μM. Therefore, DXI-NLCs constitute a promising antiproliferative therapy that has proven to be especially effective against breast cancer.

Formulation and optimization of novel dexibuprofen- Aloe vera deformable emulgels for enhanced anti-inflammatory activity

Dexibuprofen (DIBU) has been used to treat inflammation and pain caused by a range of illnesses, including arthritis. Its efficacy, however, is substantially hampered by gastric and CNS effects on its oral administration. Hence, present study is working on development of a unique topical emulgel formulation that maximises its anti-inflammatory efficacy in order to avoid its oral dosing. To begin, DIBU formulation was optimised and incorporated into Aloe vera gel base to develop Dexibuprofen Aloe vera emulgel (DAE). Following that, the anti-inflammatory activity was investigated in Wister rats as an experimental animal. Light liquid paraffin (LLP), Span 20, and Tween 20 were used to produce DIBU emulsions. Using a statistical optimization technique, central composite design, the emulsion formulation was optimised for desirable globule size and zeta potential. The physico-chemical characterization studies showed that DAEs are transparent with good homogeneity and spreadability without phase separation. Rheological studies revealed that, DAEs are non-newtonian systems with shear thinning behaviour (viscosity 98768 ± 78 to 109574 ± 54 cP). They also demonstrated remarkable bio-adhesive strength (6.4 ± 1.2 to 6.8 ± 2.2 kg/cm2) without any signs of skin irritation. Drug diffusion follows zero order kinetics with non-fickain diffusion mechanism. The pharmacodynamic testing found that the optimised DAE2 reduced paw volume by 96.5 ± 3.4% and 94.18 ± 2.8% in carrageenan and egg albumin produced edoema techniques, respectively. The findings revealed that newly created DAEs can be used as prospective topical delivery systems for DIBU to augment its anti-inflammatory impact in lieu of oral tablets for the treatment of rheumatic illnesses such as arthritis.

Mechanical Properties Improvement of Dexibuprofen through Dexibuprofen-Caffeine Co-crystal Formation by Ultrasound assisted Solution Co-crystallization Method

The ability of an active pharmaceutical ingredient to be compressed is directly affected by its mechanical properties, such as flowability and tabletability. Dexibuprofen (DXI) with poor mechanical properties has improved its flowability and tabletability by co-crystal formation with caffeine (CAF) using ultrasound assisted co-crystallization (USSC) method in chloroform solvent. The characterization of the co-crystal formation included crystal morphology, powder X-ray diffractogram, and thermal behavior. The mechanical properties testing including flowability (compressibility index) and tabletability (tensile strength and elastic recovery) were conducted on DXI-CAF co-crystal and pure DXI. The tabletability test was conducted at 10 to 60 kg/cm2 of compression force. The characterization results show that the USSC result has a unique crystal habit, diffractogram, melting point that is different from pure DXI, and this indicates the formation of DXI-CAF co-crystal. The DXI-CAF co-crystal compressibility index was in the good category, while pure DXI was in the poor category. The maximum tensile strength value of the DXI-CAF co-crystal was 1.526 MPa achieved at a compression force of 50 kg/cm2, whilst the maximum tensile strength value of pure DXI was only 0.853 MPa achieved at a compression force of 20 kg/cm2. The elastic recovery curve showed the percentage of elastic recovery of DXI-CAF co-crystal was better than pure DXI. It can be concluded that the co-crystal formation of DXI-CAF by the USSC method was able to improve the mechanical properties (flowability and tabletability) of dexibuprofen.Keywords: dexibuprofen, caffeine, ultrasound assisted co-crystallization, tensile strength, elastic recovery

Solubility and Dissolution Enhancement of Dexibuprofen with Hydroxypropylbetacyclodextrin (HPβCD) and Poloxamers (188/407) Inclusion Complexes: Preparation and In Vitro Characterization.

The objective of this study was to improve the dissolution and solubility of dexibuprofen (DEX) using hydroxypropyl beta cyclodextrin (HPβCD) inclusion complexes and also to evaluate the effect of presence of hydrophilic polymers on solubilization efficiency of HPβCD. Three different methods (physical trituration, kneading and solvent evaporation) were used to prepare binary inclusion complexes at various drug-to-cyclodextrin weight ratios. An increase in solubility and drug release was observed with the kneading (KN) method at a DEX/HPβCD (1:4) weight ratio. The addition of hydrophilic polymers poloxamer-188 (PXM-188) and poloxamer-407 (PXM-407) at 2.5, 5.0, 10.0 and 20% w/w enhanced the complexation efficiency and solubility of DEX/HPβCD significantly. Fourier-transform infrared (FTIR) analysis revealed that DEX was successfully incorporated into the cyclodextrin cavity. Differential scanning calorimetry (DSC) and X-ray diffractometry (XRD) revealed less crystallinity of the drug and its entrapment in the cyclodextrin molecular cage. The addition of PXM-188 or PXM-407 reduced the strength of the DEX endothermic peak. With the addition of hydrophilic polymers, sharp and intense peaks of DEX disappeared. Finally, it was concluded that PXM-188 at a weight ratio of 10.0% w/w was the best candidate for improving solubility, stability and release rate of DEX.

Dexibuprofen ameliorates peripheral and central risk factors associated with Alzheimer\u2019s disease in metabolically stressed APPswe/PS1dE9 mice

BackgroundSeveral studies stablished a relationship between metabolic disturbances and Alzheimer´s disease (AD) where inflammation plays a pivotal role. However, mechanisms involved still remain unclear. In the present study, we aimed to evaluate central and peripheral effects of dexibuprofen (DXI) in the progression of AD in APPswe/PS1dE9 (APP/PS1) female mice, a familial AD model, fed with high fat diet (HFD). Animals were fed either with conventional chow or with HFD, from their weaning until their sacrifice, at 6 months. Moreover, mice were divided into subgroups to which were administered drinking water or water supplemented with DXI (20 mg kg−1 d−1) for 3 months. Before sacrifice, body weight, intraperitoneal glucose and insulin tolerance test (IP-ITT) were performed to evaluate peripheral parameters and also behavioral tests to determine cognitive decline. Moreover, molecular studies such as Western blot and RT-PCR were carried out in liver to confirm metabolic effects and in hippocampus to analyze several pathways considered hallmarks in AD.ResultsOur studies demonstrate that DXI improved metabolic alterations observed in transgenic animals fed with HFD in vivo, data in accordance with those obtained at molecular level. Moreover, an improvement of cognitive decline and neuroinflammation among other alterations associated with AD were observed such as beta-amyloid plaque accumulation and unfolded protein response.ConclusionsCollectively, evidence suggest that chronic administration of DXI prevents the progression of AD through the regulation of inflammation which contribute to improve hallmarks of this pathology. Thus, this compound could constitute a novel therapeutic approach in the treatment of AD in a combined therapy.

Dexibuprofen Therapeutic Advances: Prodrugs and Nanotechnological Formulations

S-(+) enantiomer of ibuprofen (IBU) dexibuprofen (DXI) is known to be more potent than its R-(−) form and exhibits many advantages over the racemic mixture of IBU such as lower toxicity, greater clinical efficacy, and lesser variability in therapeutic effects. Moreover, DXI potential has been recently advocated to reduce cancer development and prevent the development of neurodegenerative diseases in addition to its anti-inflammatory properties. During the last decade, many attempts have been made to design novel formulations of DXI aimed at increasing its therapeutic benefits and minimizing the adverse effects. Therefore, this article summarizes pharmacological information about DXI, its pharmacokinetics, safety, and therapeutic outcomes. Moreover, modified DXI drug delivery approaches are extensively discussed. Recent studies of DXI prodrugs and novel DXI nanoformulations are analyzed as well as reviewing their efficacy for ocular, skin, and oral applications.

Formulation of solid dispersion to improve dissolution and oral bioavailability of poorly soluble dexibuprofen

Dexibuprofen (DEXI) belongs to BCS class II drug with poor aqueous solubility resulting in poor bioavailability. To enhance solubility and bioavailability of DEXI, DEXI-loaded solid dispersion (SD) was formulated. DEXI-SDs were prepared by melting method and solvent evaporation method. Amphipathic polymer poloxamer 407 (pol 407) was selected based on solubility and dissolution tests. The ratio of DEXI:pol 407 was optimized as 1:2. The physicochemical properties, dissolution, and oral bioavailability of SD3 and SD6 were evaluated to compare preparation methods. The dissolution rate of DEXI from SD formulations was higher at pH 6.8 and pH 7.2 than at pH 1.2. Following oral administration in rats, the Cmax and AUClast of SD3 and SD6 formulations were significantly higher compared with raw DEXI. In addition, the SD6 formulation showed increased Cmax and AUClast by 1.34- and 1.33-fold, compared with those of SD3 formulation, respectively. These results demonstrated that SD formulation has excellent potential as a formulation for poorly soluble drug DEXI.

HPMC-co-acrylic acid dexibuprofen once-daily oral hydrogels

The study aimed to synthesize dexibuprofen (DXIBN) solid dispersions (SDS)-loaded hydroxypropylmethylcellulose (HPMC) and co-acrylic acid (AA)-based oral hydrogels via a modest solvent evaporation technique. Free radical polymerization technique was used to prepare HPMC-co-AA hydrogels using EGDMA as cross-linker and ammonium per sulfate as initiator. SDS of DXIBN were prepared using Soluplus® (SLPS®) as a solubilizing agent. The solubility of pure DXIBN and the respective SDS was analyzed in phosphate buffer solutions (PBS) at varying pH (1.2, 6.8 and 7.4 pH) at temperatures (25 and 37 °C). The physiochemical characterizations: swelling analysis, diffusion co-efficient, porosity and sol-gel analysis, Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC), swelling behavior and release studies (at pH 1.2 and 7.4) were steered. The solubility was found to be significantly (p < .05) improved up to twofolds as compared to pure DXIBN. The hydrogels with higher concentrations of HPMC and AA showed significant (p < .05) increase in swelling, whereas there was a significant (p < .05) decrease with higher concentration of cross-linker EGDMA. The release kinetics applied trailed overall the non-Fickian release mechanism. The existing work exhibited was found to be improved DXIBN solubility using Soluplus via SDS technique and a stable HPMC-co-AA DXIBN release retardant hydrogel as an exceptional safer tool for the treatment of rheumatoid arthritis.

Comparison of Fever-reducing Effects in Self-reported Data from the Mobile App: Antipyretic Drugs in Pediatric Patients

We compared the fever-reducing efficacy of acetaminophen (AA), ibuprofen (IBU), and dexibuprofen (DEX) using data collected from the mobile healthcare application FeverCoach, which provides parents with guidelines for determining their child’s health condition, according to body temperature. Its dataset includes 4.4 million body temperature measurement records and 1.6 million antipyretics treatment records. Changes in body temperature over time were compared after taking one of three different antipyretics (AA, IBU, and DEX), using a one-way ANOVA followed by a post-hoc analysis. A multivariate linear model was used to further analyze the average body temperature differences, calibrating for the influences of age, weight, and sex. Children administered IBU had average body temperatures that were 0.18 °C (0.17–0.19 °C), 0.25 °C (0.24–0.26 °C), and 0.18 °C (0.17–0.20 °C) lower than those of children administered AA, at time intervals of 1–2 hours, 2–3 hours, and 3–4 hours, respectively. Similarly, children administered DEX had average body temperatures that were 0.24 °C (0.24–0.25 °C), 0.28 °C (0.27–0.29 °C), and 0.12 °C (0.10–0.13 °C) lower than those of children administered AA, at time intervals of 1–2, 2–3, and 3–4 hours, respectively. Although the data were collected from the application by non-professional parents, the analysis showed that IBU and DEX were more effective in reducing body temperature than AA was.

Dexibuprofen prevents neurodegeneration and cognitive decline in APPswe/PS1dE9 through multiple signaling pathways

The aim of the present study is to elucidate the neuronal pathways associated to NSAIDs causing a reduction of the risk and progression of Alzheimer's disease. The research was developed administering the active enantiomer of ibuprofen, dexibuprofen (DXI), in order to reduce associated gastric toxicity. DXI was administered from three to six-month-old female APPswe/PS1dE9 mice as a model of familial Alzheimer's disease. DXI treatment reduced the activation of glial cells and the cytokine release involved in the neurodegenerative process, especially TNFα. Moreover, DXI reduced soluble β-amyloid (Aβ1-42) plaque deposition by decreasing APP, BACE1 and facilitating Aβ degradation by enhancing insulin-degrading enzyme. DXI also decreased TAU hyperphosphorylation inhibiting c-Abl/CABLES/p-CDK5 activation signal pathway and prevented spatial learning and memory impairment in transgenic mice. Therefore, chronic DXI treatment could constitute a potential AD-modifying drug, both restoring cognitive functions and reversing multiple brain neuropathological hallmarks.

Formulation and evaluation of anti-rheumatic dexibuprofen transdermal patches: a quality-by-design approach

Dexibuprofen (DXIBN) transdermal patches were formulated using various concentrations of selected polymeric excipients (matrix material; ethyl cellulose and polyvinylpyrrolidone, plasticizer (di-N-butyl phthalate), and a conventional permeation enhancer (almond oil)). Initial patch formulations were evaluated for their physiochemical properties (thickness, moisture uptake, final moisture content, and DXIBN content). Also, impact of patch components on resulting tensile strength and in vitro permeation were used to predict an optimal patch formulation using a quality-by-design (QbD) approach, which was subsequently evaluated and further compared with a commercial oral tablet dosage form for in vitro and in vivo release (rabbit model). Initially formulated patches demonstrated uniform thickness (0.44 ± 0.02 cm), relatively low moisture uptake (7.87 ± 1.11 w/w %), and highly acceptable drug loading values (100.0 ± 0.026%). The tensile strength of patches increased significantly with matrix polymer concentration and to a lesser degree with increase in plasticizer and permeation enhancer content, although these affected the permeation of DXIBN. Predicted properties (tensile strength and DXIBN steady-state flux) for the QbD-optimized formulation were in close agreement to experimental results. The QbD optimal patch formulation behavior differed significantly from the commercial tablet formulation in vivo. Such model-based predictions (QbD approach) will reduce cost and time in formulation development sciences.

Adoption of polymeric micelles to enhance the oral bioavailability of dexibuprofen: formulation, in-vitro evaluation and in-vivo pharmacokinetic study in healthy human volunteers

This work aimed to incorporate Dexibuprofen (DXI), the pharmacologically active and more potent form of ibuprofen, into polymeric micelles based tablets with enhanced oral bioavailability. Thin film hydration technique was employed to prepare DXI polymeric micelles using Pluronic® F127 and/or P123 solutions in different ratios (ranging from 1:1 up to 1:10). Prepared micelles were characterized regarding particle size, drug loading and entrapment efficiency. Selected formulae were lyophilized in presence of cryoprotectants and subjected to solid-state characterization as well as scanning and transmission electron microscopy. Subsequently, tablets were prepared and evaluated in-vitro regarding physical properties and drug release. An in-vivo pharmacokinetic study was performed in six healthy human volunteers in comparison to the commercially available tablet of DXI. Solid-state characterization proved that DXI was homogenously dispersed in Pluronic micelles’ matrices. Formula TF5 tablets comprising lyophilized micelles (F5; DXI: Pluronic F127 in 1:1 ratio and 0.25% mannitol) showed higher Cmax and earlier tmax values than those of the commercial formula, where the relative bioavailability was calculated to be 160.15%. The experimental evidence in this research leads to the conclusion that polymeric micelles present enabling properties for oral delivery of drugs with low solubility.

Development and Validation of a HPLC and an UV Spectrophotometric Methods for Determination of Dexibuprofen in Pharmaceutical Preparations

A high-performance liquid chromatographic (HPLC) and a ultraviolet (UV) methods were developed and validated for the quantitative determination of Dexibuprofen (DI) in pharmaceutical dosage form. HPLC was carried out by reversed phase technique on a RP-18 column with a mobile phase composed of acetonitrile and 0.5% triethylamine (pH 7.5 adjusted with orthophosphoric acid (30 : 70, v/v)). UV method was performed with the λ max at 222.0 nm. Both the methods showed good linearity, reproducibility and precision. No spectral or chromatographic interferences from the tablet excipients were found in UV and HPLC. The method was successfully applied to commercial DEXIFEN tablets. Validation parameters such as linearity, precision, accuracy, and specificity were determined. The proposed method could be applicable for routine analysis of DI and monitoring of the quality of marketed drugs.

Pharmacokinetics and bioequivalence of single dose and multiple doses of immediate- and extended-release formulations of dexibuprofen in healthy Chinese subjects

To compare the pharmacokinetic (PK) profiles and bioequivalence of the extended-release (ER) and immediate-release (IR) formulations of dexibuprofen (DI) in healthy Chinese volunteers after single dose and multiple doses. Zefen® (IR capsule, containing 150 mg DI, Suzhou No.4 Pharmaceutical Factory, Jiangsu, China) and ER capsule (containing 225 mg DI, Tianjin Zhongtian Pharmaceutical Co. Ltd., Tianjin, China). This was an open, randomized, two-period crossover study. Eligible subjects were healthy male Chinese volunteers. 22 subjects were randomly assigned to receive a single 450 mg dose of the test or reference formulation on the first day. During the next 6 days, the test group received a multiple-dose of ER DI capsule (450 mg, b.i.d.) and the reference group took a multiple-dose of IR DI capsule (300 mg, t.i.d.), respectively. Multiple blood samples were collected, and plasma concentrations of DI were analyzed using high performance liquid chromatography (HPLC) system. After a 9-day washout period, the subjects were administered the alternate formulation. Bioequivalence was concluded if the 90% confidence interval (CI) for the ratio between test and reference was within accepted limits. Adverse events (AEs) were monitored and documented throughout the confinement in the clinic and washout phases of each study period. 21 subjects completed the single dose administration and 20 subjects were evaluable for the multiple doses PK parameters. Single-dose Mean AUC0-t and AUC0-inf for ER formulation were 116.14 ± 21.54 mg·h/l and 117.60 ± 22.27 mg·h/l, and for IR formulation, were 107.25 ± 23.48 mg·h/l and 108.18 ± 23.93 mg·h/l, with the 90% CI within the limits accepted for bioequivalence. Mean Cmax for ER and IR formulations were 22.30 ± 5.17 mg/l and 30.26 ± 13.54 mg/l, respectively. And median tmax for ER and IR formulations were 4.5 h and 2.0 h. The retard quotient (delta R) for ER product was 1.9 ± 0.93, which indicated an intermediate extended release effect. Multiple-dose Mean AUC0-24 for ER formulation was 217.93 ± 41.07 mg·h/l and for IR formulation was 199.33 ± 37.32 mg·h/l. Other PK parameters of ER and IR formulations were as follows: median tmax were 4.8 h and 2.0 h, Css-max were 20.21 ± 2.69 mg/l and 19.71 ± 3.46 mg/l, Css-min were 2.47 ± 0.99 mg/l and 2.48 ± 0.99 mg/l, Cav were 9.08 ± 1.71 mg/l and 8.31 ± 1.56 mg/l, respectively. This study found that in these subjects, the absorption rates of the two DI formulations were not bioequivalent, but at steady state, the daily exposure provided by less frequent DI ER dosing was not significantly different from the same daily dose with DI IR capsules, administered more frequently.