新一代促胰岛素分泌药物──Repaglinide

２型糖尿病的发病机理至今尚不清楚，因为它涉及不同程度ＩＮＳ抵抗及β—细胞功能障碍。就其ＩＮＳ抵抗和β—细胞功能障碍的病因及两者在糖尿病发生中的相对重要性，一直存在着争论。许多研究人员在重视ＩＮＳ抵抗的同时，也没有放弃对β—细胞功能障碍的研究。并研制出...

A simple method to improve the dissolution of repaglinide and exploration of its mechanism

In the present study,a simple and rapid method was developed to improve the in vitro dissolution of repaglinide,an oral antidiabetic drug,which was based on addition of meglumine in 50%(v/v)ethanol to dissolve repaglinide,and the drug dissolved in meglumine/50%ethanol was used directly with a binder to prepare tablets.The mechanism of solubilization of repaglinide by meglumine was studied by using infrared spectrum(IR),ultraviolet(UV)measurement through dual wavelength,differential scanning calorimetry(DSC)and X-ray powder diffraction methods.Dissolution tests of repaglinide tablets were performed in the media with different pH values and the repaglinide concentrations were analyzed by High Performance Liquid Chromatography(HPLC)method.The solubility data showed that with the meglumine concentration increasing,the solubility of repaglinide was increased.Meanwhile,tablets with the molar ratio of repaglinide and meglumine 1:2(n/n)resulted in a significant increase in dissolution compared to the repaglinide tablets without using meglumine,and nearly equal to the commercial preparations of Novo-Norm^(®),which concluded that meglumine had a great role in promoting the dissolution of repaglinide.The results of IR and UV dual wavelength methods suggested the formation of repaglinideemeglumine(REPeMEG)molecular complex.DSC results showed that the melting peak of repaglinide disappeared in the REPeMEG coprecipitate,which indicated that repaglinide was stable when existing at amorphous or molecular state.The experiment of X-ray powder diffraction showed that with the solubilization of meglumine,the crystal diffraction peak of repaglinide disappeared,which further inferred that repaglinide was formed complexes with meglumine.It was demonstrated that the method of improving repaglinide with meglumine was reliable and could be suitable for repaglinide tablets production in industry.This study also provides a feasible way to enhance the dissolution of drugs with low solubility,which will be leading to improved bioavailability of these drugs.

<i>In Vitro</i>and <i>in Vivo</i>(Mouse) Evaluation of Drug-Drug Interactions of Repaglinide with Anti-HIV Drugs

Repaglinide is type 2 short acting anti-diabetic drug which is primarily metabolized by CYP2C8 and CYP3A4 and is also a substrate of influx transporter OATP1B1. HIV drugs are potent inhibitors of CYP3A4 and OATP transporters. Several drug-drug interactions (DDIs) were noticed when protease inhibitors (PIs) coadministered with drugs metabolized by CYP3A4. The PIs are also potent mechanism based inhibitors, out which ritonavir is most potent. In the current study we evaluated in vitro (mouse and human liver microsomes) and in vivo DDIs of repaglinide with anti-HIV drugs. Out of the following tested drugs (Amprenavir, Indinavir, Nelfinavir, Ritonavir, Saquinavir, Delavirdine, Maraviroc, Efavirenz, Nevirapine and Ketoconazole) Amprenavir (APV), Ritonavir (RTV) and Ketoconazole (KTZ) showed inhibition of OH-repaglinide formation in human and mouse liver microsomes. The positive reversible inhibitions were further tested for irreversible inhibitions where we didn’t observe any irreversible inhibitions. In vitro inhibitions were further evaluated in the in vivo pharmacokinetics (mouse) where repaglinide pharmacokinetics was altered by RTV and KTZ. The DDIs in both studies were very strong;the dose of repaglinide is reduced to 20 fold. In conclusion, there could be possible DDIs when RTV dosed with repaglinide;we have also demonstrated that mouse could be useful preclinical tool when used in conjunction with in vitro screening models for DDIs.

Liquid Chromatography Tandem Mass Spectrometry Method for Determination of Anti-Diabetic Drug Repaglinide in Human Plasma

A highly sensitive, accurate and rapid analytical method based on reversed-phase liquid chromatography/electrospray ionization tandem mass spectrometry (RP-LC-ESI-MS/MS) has been developed and validated for the determination of repaglinide in human plasma using cetirizine as an internal standard (IS). The method was validated over a linear range of 0.5 - 100 ng/ml. After addition of IS, analytes were extracted from the plasma samples by liquid-liquid extraction using tert-butyl methyl ether as. The dried residue was reconstituted with 500 μL of mobile phase consisting of water/methanol/acetonitrile (62.5:20:17.5, v/v/v) and 0.2% formic acid. Chromatographic separations were achieved on a C18 analytical column. The analytes were detected with a triple quadrupole mass spectrometer using turbo V? ion spray source with positive ionization in multiple reaction monitoring (MRM) mode using MRM transitions m/z 453.3 > 162.2 and m/z 389.0 > 201.1 for the drug and IS, respectively. The proposed method was fully validated in terms of linearity, accuracy, precision, specificity, sensitivity, recovery and stability, giving results within the acceptable range. This method was successfully applied for a large number of authentic human plasma samples from a bioequivalence study.

Association between Sex Differences and the Pharmacokinetics of Repaglinide among a Malaysian Population

This study was conducted to evaluate the effect of sex differences on the pharmacokinetics of repaglinide in healthy subjects. One hundred twenty one healthy volunteers (61 male and 60 female;aged 18 - 50 years) were included in the study. Subjects were administered a single 4-mg repaglinide oral dose. Blood samples were taken at 0, 30, 60, 120, 180 and 240 min. Serum repaglinide levels were determined by a high-performance liquid chromatography (HPLC) method. Subjects were also genotyped by polymerase chain reactions - restriction fragment length polymorphisms (PCR-RFLP) for CYP3A4*4, *5 and *18 alleles and by an allele-specific multiplex PCR for CYP2C8*2, *3, *4 and *5 alleles. The pharmacokinetics of repaglinide were comparable between male and female subjects. The mean clearance (CL) of repaglinide was 16.0% lower (p = 0.03), the mean area under the serum concentration-time curve (AUC) was 12.8% higher (p = 0.04) and the peak serum concentration (Cmax) was 13.2% higher (p = 0.03) in females compared to male subjects. The mean rate of elimination (kel) and mean CL of repaglinide were 47.67% (p = 0.03) higher and 29.25% (p = 0.03) higher, respectively, in male subjects having CYP2C8*5 allele compared to female subjects. We also found that the mean half-life (t1/2) of repaglinide was 42.43% higher (p = 0.03), and the mean AUC was 35.83% higher (p = 0.03) in female subjects when compared to the male subjects having CYP2C8*5 allele. Sex differences significantly influence the pharmacokinetics of repaglinide.

Derivative Spectrophotometric and Isocratic High Performance Liquid Chromatographic Methods for Simultaneous Determination of Repaglinide and Metformin Hydrochloride in Pharmaceutical Preparations

In this study, a derivative spectrophotometric method and one HPLC method were developed and validated for analysis of anti-diabetic drugs, repaglinide (RPG) and metformine hydrochloride (MTF) in tablets. The spectrophotometric methods were based on zero-crossing first-derivative and fourth-derivative spectrophotometric method for simultaneous analysis of RPG (308 nm) and MTF (267 nm), respectively. Linear relationship between the absorbance at λmax and the drug concentration was found to be in the ranges of 5.0 - 50.0 μg·mL-1 for both RPG and MTF. The quantification limits for RPG and MTF were found to be 0.568 and 1.156 μg·mL-1, respectively. The detection limits were 0.170 and 0.347 μg·mL-1 for RPG and MTF, respectively. The second method is a rapid stability-indicating isocratic HPLC method developed for the determination of RPG and MTF. A linear response was observed within the concentration range of 5.0 - 50.0 μg·mL-1 for both RPG and MTF. The quantification limits for RPG and MTF were found to be 1.821 and 1.653 μg·mL-1, respectively. The detection limits were 0.601 and 0.545 μg·mL-1 for RPG and MTF, respectively. The proposed methods were successfully applied to the tablet analysis with good accuracy and precision.

Effect of repaglinide and gliclazide on glycaemic control, early-phase insulin secretion and lipid profiles in newly diagnosed type 2 diabetics

Background Both repaglinide and gliclazide are insulin secretagogues widely used in the treatment of type 2 diabetes.They stimulate insulin secretion through distinct mechanisms and may benefit patients from different aspects.The present study was to evaluate the effects of repaglinide or gliclazide on glycaemic control,insulin secretion,and lipid profiles in type 2 diabetes patients.Methods A total of 47 newly diagnosed type 2 diabetes patients were randomized 1：1 to receive a 4-week treatment with repaglinide or gliclazide.The standard mixed meal tolerance test was performed before and after the treatment.Plasma glucose （PG）,insulin concentration,and lipid profiles were measured.The area under insulin concentration curve （AUCins） and the early-phase insulin secretion index （△I30/△G3o） were calculated.Results After the trial,fasting and postprandial PG and postprandial insulin improved significantly in both groups （P〈0.05）.The maximum insulin concentration occurred earlier in the repaglinide group than that in the gliclazide group.AUCins increased in both groups （P 〈0.05）,but no significant difference was found between groups.△I30/△G30 increased in both groups （P 〈0.05）,especially in the repaglinide group （P 〈0.05）.Triglyceride and total cholesterol decreased significantly in the repaglinide group in some time points,while no significant change was observed in the gliclazide group.Conclusions Repaglinide and gliclazide had similar effects on glycaemic control and total insulin secretion,while repaglinide had more effects on improvements in β-cell function and lipid metabolism.

Determination of repaglinide in human plasma by high-performance liquid chromatography–tandem mass spectrometry

A rapid and sensitive method based on high-performance liquid chromatography–tandem mass spectrometry(LC–MS/MS)has been developed for the determination of repaglinide in human plasma.The analyte and internal standard(I.S.),diazepam,were extracted from plasma(25 mL)by liquid–liquid extraction with diethyl ether–dichloromethane(60:40,v/v)and separated on a XDB-C_(18) column using acetonitrile–ammonium acetate buffer(pH 6.8,0.01 mol/L)as mobile phase.The retention times of repaglinide and I.S.were 1.95 and 2.35 min,respectively.Detection was carried out using API 4000 mass spectrometer with an ESI interface operating in the multiple reaction monitoring(MRM)mode.The assay was linear over the concentration range 0.050–50 ng/mL with a limit of detection(LOD)of 0.010 ng/mL.Intra-and inter-day precisions(as relative standard deviation,R.S.D.)were ≤5.07%and ≤11.2%,respectively,and accuracy(as relative error,R.E.)was from-0.593%to -1.26%.The assay was successfully applied to a pharmacokinetic study involving a single oral administration of a tablet containing 2 mg repaglinide to each of 10 healthy volunteers.

High performance liquid chromatography with immobilized Ru(bpy)_3^(2+)-KMnO_4 chemiluminescence detection and its application in metabolism of repaglinide in pig liver microsomes

A novel high performance liquid chromatography-chemiluminescence（HPLC-CL） method for investigation of in vitro metabolism of repaglinide in pig liver microsomes with microdialysis sampling technique was developed.The chromatographic separation was performed on a Hypersil BDS-C18 column with an isocratic mobile phase consisting of methanol and 0.01 mol/L KH_2PO_4（pH 3.0）（volume ratio 75：25） at a flow rate of 1.0 mL/min.The detection was based on the chemiluminescence reaction of repaglinide with acidic potassium permanganate（KMnO_4） and tris（2,2＇-bipyridyl）ruthenium（Ⅲ）（Ru（bpy）_3^（3＋））,which was immobilized on the cationic ion-exchange resin for obtaining high sensitivity and reducing consumption of expensive reagent.

Study on the interactions of pharmacokinetics and liver distributions between rosuvastatin and repaglinide in rats

In the present study,we aimed to investigate the interactions of pharmacokinetics and liver distributions between rosuvastatin and repaglinide in rats.Coadministration of repaglinide（0.5 mg/kg,1 mg/kg and 2 mg/kg） for 7 d significantly increased the AUC0–24 and Cmax of rosuvastatin（P〈0.01）,but dramatically decreased the CL/F of rosuvastatin（P〈0.01） after a single dose of rosuvastatin（10 mg/kg）.There were no obviously changes in the parameters of Tmax and t1/2.Coadministration of repaglinide also decreased the liver distribution of rosuvastatin（P〈0.01）.Coadministration of rosuvastatin（20 mg/kg） for 7 days significantly increased the AUC0–12 and Cmax of repaglinide（P〈0.05）,and decreased the CL/F of repaglinide（P〈0.01） after a single dose of repaglinide（1 mg/kg）.The liver distribution of repaglinide was also decreased（P〈0.01）.Our animal study indicated that repaglinide could significantly affect the pharmacokinetics and liver distribution of rosuvastatin in rats and vice versa.

Simultaneous determination of Repaglinide and Irbesartan in biological plasmas using micellar enhanced excitation-emission matrix fluorescence coupled with ATLD method

A highly sensitive and selective 3D excitation-emission fluorescence method has been proposed to rapidly quantify the combined antidiabetics Repaglinide(Re) and Irbesartan(Ir) in rat and human plasmas with the aid of second-order calibration method based on alternating trilinear decomposition(ATLD) method. Re and Ir with weak fluorescence can be endowed with strong fluorescent property by changing the microenvironment in samples and improving the fluorescence quantum yield by using an appropriate micellar enhanced surfactant. The enhanced excitation-emission matrix fluorescence of Re and Ir can be accurately resolved and can simultaneously attain the optimal concentration even in the presence of a potentially strong intrinsic fluorescence from complex biological matrices, such as rat and human plasmas, by using the ATLD method, which completely exploits the "second-order advantage". The average recoveries of Re and Ir obtained from ATLD with the factor number of 3(N=3) were 101.0%±4.3% and 99.1%±4.1% for rat plasma and 100.5%±5.4% and 97.1%±3.6% for human plasma. Several statistical methods, including Student's t-test, figures of merit, and elliptical joint confidence region, have been utilized to evaluate the accuracy of the proposed method. Results show that the developed method can maintain second-order advantage in simultaneous determinations of the weak fluorescent analytes of interest in different biological plasma matrices.

2型糖尿病运用瑞格列奈治疗的效果观察

为了推进分级诊疗,逐步完善社区首诊、双向转诊、分级诊疗的服务模式,提供三师共管慢病精细化管理服务。在我们基层的社区医院,推行了家庭医生签约服务,实行了慢病管理对2型糖尿病运用瑞格列奈疗效观察。方法:家庭医生签约服务时,对入户签约的2型糖尿病患者随机分成2组,每组47人。治疗方案为对照组采用胰岛素治疗和研究组采用胰岛素治疗的基础上,加用瑞格列奈进行治疗。对比分析两组患者的治疗疗效和发生的不良反应情况进行比对。结果提示:治疗疗效对比,研究组比对照组疗效好,差异具有统计学意义(P<0.05)。不良反应发生情况对比,研究组患者比对照组患者不良反应发生率低,差异具有统计学意义(P<0.05)。结论:2型糖尿病患者采用瑞格列奈治疗,能够有效的提升患者的治疗疗效,减少患者并发症和不良反应的发生,值得推广应用。

Efficacy and safety of metformin and sitagliptin based triple antihyperglycemic therapy(STRATEGY):a multicenter,randomized,controlled,non-inferiority clinical trial

Despite the current guideline's recommendation of a timely stepwise intensification therapy,the "clinical inertia",termed as the delayed treatment intensification,commonly exists in the real world,which may be partly due to the relatively little substantial evidence and no clear consensus regarding the efficacy and safety of triple oral agents in patients inadequately controlled with dual therapy.In this clinical trial performed in 237 centers in China,5,535 type 2 diabetic patients inadequately controlled by previous therapies were treated with a stable metformin/sitagliptin dual therapy for 20 weeks.The patients who did not reach the glycated hemoglobin A1c(HbA1c) goal were then further randomized into glimepiride,gliclazide,repaglinide,or acarbose group for an additional 24-week triple therapy.A mean HbAlc reduction of 0.85%was observed when sitagliptin was added to the patients inadequately controlled with metformin in 16 weeks.Further HbAlc reductions in the 24-week triple therapy stage were 0.65%in glimepiride group,0.70%in gliclazide group,0.61%in repaglinide group,and 0.45%in acarbose group.The non-inferiority criterion for primary hypotheses was met for gliclazide and repaglinide,but not for acarbose,compared with glimepiride,when added to metformin/sitagliptin dual therapy.The incidences of adverse events(AEs) were 29.2%in the dual therapy stage and30.3%in the triple therapy stage.Metformin/sitagliptin as baseline therapy,with the addition of a third oral antihyperglycemic agent,including glimepiride,gliclazide,repaglinide,or acarbose,was effective,safe and well-tolerated for achieving an HbAlc<7.0%goal in type 2 diabetic patients inadequately controlled with previous therapies.The timely augmentation of up to three oral antihyperglycemic agents is valid and of important clinical benefit to prevent patients from exposure to unnecessarily prolonged hyperglycemia.