A promising choice in hypertension treatment: Fixed-dose combinations

Obtaining the target blood pressure level by monotherapy can be challenging currently, especially for the patients who are suffering from other diseases meanwhile. It is demonstrated that a majority of hypertensive patients need two or more antihypertensive drugs to lower their blood pressure effectively. Consequently, fixed-dose which can be defined as that several active agents were combined in single pharmaceutical formulations appears to be a novel and underlying power in overcoming the cardiovascular disease. Based on the analysis of some literature and relative data from FDA, the advantages of fixed-dose combination are elucidated and formulations of common dual, triple-combinations were summarized. Clinical practices proved that fixed-dose combinations had many benefits comparing with single drug and separate agents in terms of effects, convenience, compliance, and costs to a certain extent. From the patients' perspective, the fixed-dose combination therapy will be increasingly utilized in blood pressure control in the future

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 1H-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 μl. 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 (R2) 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

Pharmacokinetics of oxiracetam and its degraded substance (HOPAA) after oral and intravenous administration in rats

The pharmacokinetics of oxiracetam and its degraded substance (4-hydroxy-2-oxo-1-pyrrolidine acetic acid, HOPAA) after oral and intravenous administration in rats were studied using an established UPLC-MS/MS method. Three groups of rats after an overnight fasted received 10 g/kg (n = 6) oxiracetam suspensions orally, and 2 g/kg (n = 6) normal or degraded oxiracetam injections intravenously via a caudal tail vein, respectively. Before the pharmacokinetic experiment, a simple safety evaluation test was conducted on the degraded oxiracetam injections containing 16.16% HOPAA in mice. There was no mortality by a single intravenous dose of 2 g/kg of degraded oxiracetam injections within two weeks, demonstrating that HOPAA was non-toxic in mice. Following intravenous administration of the normal injections, the plasma concentration-time curves of oxiracetam and HOPAA both showed a rapid elimination phase. The values of t1/2 were 3.1 ± 1.5 h for oxiracetam and 0.8 ± 0.2 h for HOPAA, and the mean residence times (MRT) were 1.2 ± 0.1 h and 0.8 ± 0.1 h, respectively. Oxiracetam and HOPAA after intravenous administration of the degraded oxiracetam injections presented elimination patterns similar to those observed in the normal injections. Oral pharmacokinetic results showed that the Tmax was less than 1.5 h for the two analytes, and both had a longer t1/2 and MRT than those of intravenous administration. Contents of HOPAA in three groups were calculated based on AUC0–t values of the two analytes. The quantitative change of HOPAA in vivo was also evaluated by comparing the plasma concentrations of HOPAA and oxiracetam at the same time for every group. Additionally, the values of absolute bioavailability of oxiracetam were about 8.0% and 7.4% calculated by the normal or degraded oxiracetam injections, which were far less than the value of 75% reported in literature, indicating the necessity of further study

Development and validation of a rapid and sensitive UHPLC–MS/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 chromatography–tandem mass spectrometry (UHPLC–MS/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 C18 column (2.1 × 50 mm, 2.6 μm) 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

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 push–pull 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 tri-layer 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

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

AbstractCombinational 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 crossover-Latin 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