Evaluation of pharmacokinetics underlies the collaborated usage of lamivudine and oxymatrine in beagle dogs

Combinational therapy of lamivudine and oxymatrine has been employed in the battle against hepatitis B virus in clinical setting. However, the pharmacokinetic behavior of the drug or active metabolism in intravenous/oral co-administration regime is poorly investigated. Herein,we evaluated the pharmacokinetic characteristic through a tailor-designed 3 way crossoverLatin square experiment in adult male beagle dogs. Six dogs were randomly treated by intravenous administration of lamivudine(2.5 mg/kg), oxymatrine(15 mg/kg) and combinational dosage, named as intravenous regime. Meanwhile the other six dogs were orally administrated with lamivudine(2.5 mg/kg), oxymatrine(15 mg/kg) and combinational dosage,named as oral regime. The pharmacokinetic feature in simultaneous oral treatment appeared to have no significant difference when compared with individual administration,even including matrine, the active metabolite of oxymatrine. In intravenous regime, the main pharmacokinetic parameters of simultaneous administration were nearly consistent with intravenous regime remedy. The collaborated application of lamivudine and oxymatrine contributed to non-distinctive pharmacokinetic fluctuations of beagle dogs in intravenous/oral regime, compared with individual employment, which established a vital base for the clinical co-administration against hepatitis B. Furthermore, the present study demonstrated that the determination of pharmacokinetics between combinational and individual therapy might assist in the development of drug compatibility in clinical therapy.

Can semipermeable membranes coating materials influence in vivo performance for paliperidone tri-layer ascending release osmotic pump tablet:In vitro evaluation and in vivo pharmacokinetics study

One purpose of this study was to develop a paliperidone(PAL)tri-layer ascending release pushepull osmotic pump(TA-PPOP)tablet which could meet the needs of clinical applications.And another purpose was to investigate whether different coating materials influenced in vivo performance of TA-PPOP.The ascending release mechanism of this trilayer delivery system on theory was elaborated.TA-PPOP was prepared by means of coating with cellulose acetate(CA)or ethyl cellulose(EC).Several important influence factors such as different core tablet compositions and different coating solution ingredients involved in the formulation procedure were investigated.The optimization of formulation and process was conducted by comparing different in vitro release behaviors of PAL.In vitro dissolution studies indicated that both the two formulations of different coating materials were able to deliver PAL at an ascending release rate during the whole 24 h test.The in vivo pharmacokinetics study showed that both self-made PPOP tablets with different coating had a good in vitro-in vivo correlation(IVIVC)and were bioequivalent with the brand product,which demonstrated no significant influence of the coating materials on the in vivo release acceleration of TA-PPOP.

A developed HPLC method for the determination of Alogliptin Benzoate and its potential impurities in bulk drug and tablets

Alogliptin(AGLT),active ingredient of Alogliptin Benzoate(AGLT-BZ),is a new dipeptidyl peptidase-4(DPP-4)inhibitor for the treatment of type 2 diabetes.This study aimed to build a suitable method to determine the potential related substances in AGLT-BZ bulk drug and tablets.Seven related substances in Alogliptin Benzoate substances were synthetized and identified by ^(1)H-NMR and ESI-MS.In addition,the impurities were detected by a gradient reverse-phase high performance liquid chromatography(RP-HPLC)with UV detection.The chromatographic system consisted of an Angilent Zobax SB-CN column(250×4.6 mm;5 μm).The mobile phase consisted of water/acetonitrile/trifluoroacetic acid 1900:100:1 v/v/v(solution A)and acetonitrile/water/trifluoroacetic acid 1900:100:1 v/v/v(solution B)using a gradient program at a flow rate of 1.0 ml/min with 278 nm detection and an injection volume of 20 ml.Additionally,selectivity,the limit of quantitation(LOQ)and limit of detection(LOD),linearity,accuracy,precision and robustness were determined.Linearity was good over the concentration range 50-1000 ng/ml and the coefficient of determination(R^(2))were 0.9991-0.9998.RSD% of the determination of precision were <2%(n=6).The method of RP-HPLC for the determination of impurities in AGLT-BZ was proved to be precise,accurate,robust and reliable.Three batches of self-made bulk drug and three dosages of commercial tablets were detected with this method.

Development and validation of a rapid and sensitive UHPLCeMS/MS method for the determination of paliperidone in beagle dog plasma

In order to evaluate the pharmacokinetic profile of paliperidone extended-release tablets in vivo,a simple and rapid ultra-high performance liquid chromatographyetandem mass spectrometry(UHPLCeMS/MS)method was developed and validated for the determination of paliperidone in beagle dog plasma.Paliperidone and diazepam(internal standard)were extracted from plasma samples with diethyl ether,and then separated on a C_(18) column(2.1×50 mm,2.6 mm)under gradient elution with methanol-0.1%formic acid at a flow rate of 0.3 ml/min.The compounds were detected using a triple-quadrupole mass spectrometer equipped with an electrospray ionization(ESI)source.The validated method was linear over the concentration range of 1.00-1000.00 ng/ml and the lower limit of quantitation was 1.00 ng/ml.The intra-day and inter-day precision values were not more than 15%(relative standard deviation<20%at low levels),while the accuracy was within±10%of nominal values.The validated UHPLC-MS/MS method was successfully applied to an oral pharmacokinetic study of paliperidone extended-release tablets in a beagle dog.

Preparation, optimization and in vitro–in vivo investigation for capsules of the choline salt of febuxostat

The objective of the present study was to exhibit the enhanced water-solubility and in vivo oral absorption when febuxostat(FXT) became the salt formation of choline. The formation of the choline salt of febuxostat was confirmed by X-ray powder diffraction, infrared spectroscopy analysis and differential scanning calorimetry. The direct filling method was used to develop a capsule formulation. Cellactose 80 was used as the filler due to its good fluidity, while cross-linked polyvinylpyrrolidone(PVPP) and magnesium stearate(MS) were used as the disintegrant and lubricant, respectively. Then the in vitro release of the formulation was carried out in five different dissolution media including HCl solution(pH 1.2),acetate buffer(pH 4.5), phosphate buffer(pH 6.8 and pH 7.2) and water. Evident improvement of release for choline febuxostat(CXT) was presented in water while the dissolution degree was decreased for CXT in the medium of phosphate buffer(pH 6.8) in comparison with FXT. Furthermore, the pharmacokinetics of CXT was studied in rats using UPLC-MS/MS compared with FXT. The data acquired illustrated that AUC0-24 h of CXT and FXT were22,245.96 ± 7342.92 μg·h/l and 12,249.70 ± 2024.04 μg·h/l, respectively. The relative bioavailability of CXT to FXT was about 181.6% and the P value of AUC0-24 h was less than 0.05. It showed significant difference between the two drugs after oral administration. In conclusion, the water-solubility and oral bioavailability were both improved remarkably for the choline salt of febuxostat and choline salinization was proved an effective way to increase the in vivo absorption for FXT.

Elaborately engineering of lipid nanoparticle for targeting delivery of siRNA and suppressing acute liver injury

Small interfering RNA(siRNA)-based gene silencing has been considered as a potential therapy modality against inflammatory diseases.Nevertheless,the effective delivery of siRNA to desired destination still remains challenging due to poor stability,high molecular weight and negative charge.Currently,ionizable lipid nanoparticle(LNP)has been extensively used as vector for effective delivery of siRNA.Herein,we report a mannose-modified LNP(M-MC_(3) LNP@TNFα)loading tumor necrosis factorα(TNFα)siRNA for targeting liver macrophages,achieving effectively inhibit acute liver injury.The M-MC_(3) LNP@TNFαnot only increases the internalization of LNP by macrophages,but also enhances the gene silencing efficiency of TNFαin vitro.Additionally,the M-MC_(3) LNP@TNFαexhibits higher accumulation in liver of healthy mice than that of MC_(3) LNP@TNFα(un-modified LNP)owing to the targeting effect of mannose.As expected,the M-MC_(3) LNP@TNFαsignificantly suppresses the expression of TNFαand ameliorates liver damage in acute liver injury model.Such a LNP targeting siRNA delivery holds great potential for the treatment of diseases associated with liver in the future.

Self-adaptive non-covalent albumin-binding near-infrared probe conjugates enabling precise sentinel lymph node metastasis illumination and primary tumor imaging

Tumor sentinel lymph node(SLN)metastasis plays a vital role in tumor staging and therapeutic decision-making process.However,precise diagnosis of primary tumors and lymphatic metastases is still hindered by low imaging resolution and poor photostability of fluorescent probes.Herein,we report three novel IR820-fatty acid(FA)conjugates(IR-OA,IR-LA,and IR-PA)for precise lymphatic metastasis illumination and primary tumor diagnosis.The IR-FA conjugates are able to non-covalently bound to albumin in vivo,and the fluorescence quantum yield is significantly enhanced after incubation with bovine serum albumin(BSA)in vitro.Moreover,the BSA-IR-FA conjugates display large Stokes shift(>120 nm),dramatically improving in vivo imaging resolution.Among them,IR-PA demonstrates distinct advantage over IR-OA,IR-LA,and IR-maleimide(MAL)(fluorescent probe previously reported by our group)in terms of fluorescence quantum yield,photostability,and imaging resolution.As a result,IR-PA exhibits satisfactory imaging results with high fluorescence intensity and imaging resolution in sentinel lymph node metastasis illumination and primary tumor location.Our findings provide a self-adaptive albumin-binding near-infrared probe conjugate for accurate diagnosis of primary tumors and lymphatic metastases.