Single Ascending Dose Study to Assess Pharmacokinetic Linearity, Safety, and Tolerability of Trimetazidine - Modified Release in Healthy Human Subjects.

AIM: This study assessed the linearity of pharmacokinetics (PK) of trimetazidine (TMZ) modified-release tablets (indicated in adults as an add-on therapy for stable angina pectoris) and measured its renal elimination, safety, and tolerability in healthy subjects. METHODS: This was a randomized, open-label, single-ascending dose study in healthy subjects. Subjects were administered with a single dose of 35, 70, or 105 mg TMZ-modified release tablets (six subjects each). Pharmacokinetic evaluations and safety analysis were performed before the first dose and till 48 h post-first dose. RESULTS: Following administration of 35, 70, and 105 mg TMZ-modified release; the Cmax (mean±SD) was 79.32 (±23.08), 153.17 (±23.08), and 199.67 (±23.08) ng/mL, the Tmax was 5.42 (±0.49), 4.51 (±1.27), and 4.57 (±0.96) h, t1/2 was 7.75 (±1.62), 6.40 (±1.23), and 6.50 (±1.18) h, AUC(0-inf) was 1116.89 (±378.35), 1838.39 (±284.50), and 2504.84 (±348.35) ng.h/mL, CLR was 13.70 (±2.24), 14.80 (±5.91), and 19.58 (±6.24) L·h-1 and CL/F was 33.69 (±8.51), 38.85 (±6.15), and 42.74 (±7.10) L·h-1, respectively. Slope estimates for AUC(0-inf), AUC(0-t), and Cmax were less than 1. Corresponding 95% CI of the slope for the AUC parameters excluded 1, indicating that the deviation from dose-proportionality was statistically significant. Corresponding 95% CI of the slope for Cmax included 1, indicating that the less than dose-proportional increase in Cmax was not statistically significant. No significant adverse events were observed. CONCLUSION: Substantial deviation from a dose-proportional increase in AUC(0-inf) and AUC(0-t) suggested a non-linear PK for TMZ-modified release. Single dose of TMZ-modified release was well tolerated and safe.

Effect of age and renal impairment on the pharmacokinetics and safety of trimetazidine: An open-label multiple-dose study.

This study evaluated the effect of age and renal impairment on pharmacokinetics of trimetazidine (TMZ) in healthy elderly and renally impaired subjects and assess safety and tolerability. In this open-label, multi-dose study, 73 subjects were divided into six treatment groups: (1) 55-65 years; (2) 66-75 years; (3) >75 years (dosing for groups 1-3 [healthy]: B.D. for 4 days), (4) mild renally impaired (dosed B.D. for 8 days); (5) moderate renally impaired (dosed O.D. for 8 days); and (6) severe renally impaired-no dialysis (dosed once every 48 h for 8 days). Blood and urine samples were collected and analyzed. The geometric least squares mean ratios for; Group 2 and 1 of AUC(0-τ)ss was 112.2 (90% CI; 92.0-136.8) and Cmax,ss was 109.9 (89.6-134.8), Group 3 and 1 of AUC(0-τ),ss was 140.5 (115.9-170.3) and Cmax,ss was 137.8 (112.9-168.2), Group 4 and 1 of AUC(0-τ),ss was 114.2 (90.3-144.4) and Cmax,ss was 120.8 (92.5-157.8), Group 5 and 1 of; AUC(0-τ),ss was 213.0 (153.1-296.3) and Cmax,ss was 123.3 (92.2-164.7) and Group 6 and 1 of AUC(0-τ),ss was 247.4 (197.8-309.6) and Cmax,ss was 95.6 (73.0-125.1). Significant increase in systemic exposure of TMZ was observed in subjects; over 75 year's age and renally impaired compared to healthy subjects. TMZ was safe and well-tolerated.

Overcoming interference of plasma phospholipids using HybridSPE for the determination of trimetazidine by UPLC-MS/MS.

An improved, precise and reliable ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method has been developed for the quantification of trimetazidine, using trimetazidine-d8 as the internal standard (IS). Interference owing to plasma phospholipids during sample preparation was overcome using a hybrid solid-phase extraction-phospholipid ultra cartridge. The mean extraction recovery of trimetazidine (98.66%) and trimetazidine-d8 (97.63%) from spiked plasma was consistent and reproducible. Chromatographic analysis was performed on a UPLC Ethylene Bridged Hybrid (BEH) C18 (50 × 2.1 mm, 1.7 µm) column with isocratic elution using acetonitrile-5 mm ammonium formate, pH 3.5 (40:60, v/v) as the mobile phase. The parent → product ion transitions for trimetazidine (m/z 267.1 → 181.1) and trimetazidine-d8 (m/z 275.2 → 181.1) were monitored on a triple quadrupole mass spectrometer with electrospray ionization functioning in the positive multiple reaction monitoring mode. The linearity of the method was established in the concentration range of 0.05-100 ng/mL for trimetazidine. The intra-batch and inter-batch accuracy and precision (CV) were 97.3-103.1 and 1.7-5.3%, respectively. Qualitative and quantitative assessment of matrix effect showed no interference of endogenous/exogenous components. The developed method was used to measure plasma trimetazidine concentration for a bioequivalence study with 12 healthy subjects.

Rationale and benefits of trimetazidine by acting on cardiac metabolism in heart failure.

Heart failure is a systemic and multiorgan syndrome with metabolic failure as a fundamental mechanism. As a consequence of its impaired metabolism, other processes are activated in the failing heart, further exacerbating the progression of heart failure. Recent evidence suggests that modulating cardiac energy metabolism by reducing fatty acid oxidation and/or increasing glucose oxidation represents a promising approach to the treatment of patients with heart failure. Clinical trials have demonstrated that the adjunct of trimetazidine to the conventional medical therapy improves symptoms, cardiac function and prognosis in patients with heart failure without exerting negative hemodynamic effects. This review focuses on the rationale and clinical benefits of trimetazidine by acting on cardiac metabolism in heart failure, and aims to draw attention to the readiness of this agent to be included in all the major guidelines dealing with heart failure.

Mucoadhesive elementary osmotic pump tablets of trimetazidine for controlled drug delivery and reduced variability in oral bioavailability.

The objectives of this work was preparation and evaluation of the mucoadhesive elementary osmotic pump tablets of trimetazidine hydrochloride to achieve desired controlled release action and augmentation of oral drug absorption. The drug-loaded core tablets were prepared employing the suitable tableting excipients and coated with polymeric blend of ethyl cellulose and hydroxypropyl methylethylcellulose E5 (4:1). The prepared tablets were characterized for various quality control tests and in vitro drug release. Evaluation of drug release kinetics through model fitting suggested the Fickian mechanism of drug release, which was regulated by osmosis and diffusion as the predominant mechanism. Evaluation of mucoadhesion property using texture analyzer suggested good mucoadhesion potential of the developed osmotic systems. Solid state characterization using Fourier-transform infrared spectroscopy, differential scanning calorimetry and powder X-ray diffraction spectroscopy confirmed the absence of any physiochemical incompatibilities between drug and excipients. Scanning electron microscopy analysis showed the smooth surface appearance of the coated tablets with intact polymeric membrane without any fracture. In vivo pharmacokinetic studies in rabbits revealed 3.01-fold enhancement in the oral bioavailability vis-à-vis the marketed formulation (Vastarel MR®). These studies successfully demonstrate the bioavailability enhancement potential of the mucoadhesive elementary osmotic pumps as novel therapeutic systems for other drugs too.

Doping control analysis of trimetazidine and characterization of major metabolites using mass spectrometric approaches.

Since January 2014, the anti-anginal drug trimetazidine [1-(2,3,4-trimethoxybenzyl)-piperazine] has been classified as prohibited substance by the World Anti-Doping Agency (WADA), necessitating specific and robust detection methods in sports drug testing laboratories. In the present study, the implementation of the intact therapeutic agent into two different initial testing procedures based on gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) is reported, along with the characterization of urinary metabolites by electrospray ionization-high resolution/high accuracy (tandem) mass spectrometry. For GC-MS analyses, urine samples were subjected to liquid-liquid extraction sample preparation, while LC-MS/MS analyses were conducted by established 'dilute-and-inject' approaches. Both screening methods were validated for trimetazidine concerning specificity, limits of detection (0.5-50 ng/mL), intra-day and inter-day imprecision (<20%), and recovery (41%) in case of the GC-MS-based method. In addition, major metabolites such as the desmethylated trimetazidine and the corresponding sulfoconjugate, oxo-trimetazidine, and trimetazidine-N-oxide as identified in doping control samples were used to complement the LC-MS/MS-based assay, although intact trimetazidine was found at highest abundance of the relevant trimetazidine-related analytes in all tested sports drug testing samples. Retrospective data mining regarding doping control analyses conducted between 1999 and 2013 at the Cologne Doping Control Laboratory concerning trimetazidine revealed a considerable prevalence of the drug particularly in endurance and strength sports accounting for up to 39 findings per year.

Hollow fiber-based liquid membrane microextraction combined with high-performance liquid chromatography for extraction and determination of trimetazidine in human plasma.

A hollow fiber-based liquid phase microextraction strategy combined with high-performance liquid chromatography was evaluated for the quantitative determination of trimetazidine in human plasma. Trimetazidine was extracted from a 2.1 mL basified plasma sample (donor phase) into the organic solvent (n-octanol) impregnated in the pores of a hollow fiber and then extracted into an acidic solution (acceptor phase) inside the lumen of the hollow fiber. The result showed that transport of drugs from alkaline sample solution into 0.5 m HCl occurred efficiently when 25 µL of 250 mm sodium 1-octanesulfonate was added into the donor phase. Several parameters influencing the efficiency of the method, such as the nature of organic solvent used to impregnate the membrane, compositions of donor phase and acceptor phase, type and concentration of carrier, extraction time, stirring rate and salt concentration, were investigated and optimized. Under the optimal conditions, the calibration curves were obtained in the range of 5-200 ng/mL with reasonable linearity (r > 0.9980). The method was successfully applied to determine the concentration of trimetazidine in human plasma.

[Adherence of patients with stable angina to treatment with trimetazidine MR and frequency of emergency medical care: results of the EFFECT study].

The adherence of patients with stable angina to antianginal therapy is the key factor of controlling the disease. The purpose of the study was to evaluate the relationship of adherence of patients with stable angina to treatment with trimetazidine modified release (MR) with frequency (risk) of emergency medical care. We consistently included in the study patients with stable angina in primary health care. The results of treatment for 16 weeks were monitored at patients with angina attacks three times per week or more, use of short nitrate and treatment with generic trimetazidine. To strengthen the antianginal therapy generic was replaced with original trimetazidine MR. Adherence is considered relatively high while taking 80-120% of the recommended dose of the drug (70 mg/day). The effectiveness of treatment evaluated by the frequency of emergency hospitalizations and/or ambulance calls because of the pain, discomfort, tightness in the chest or ischemic changes on the electrocardiogram. 870 patients were included in the study, the results of treatment in 185 were assessed. Patients with a relatively high adherence to trimetazidine MR (n=151) were used (median) 99% (98, 104), with low (<80%, n=34) adherence - 67% (49, 76) of the recommended dose of the drug. During the study period, the primary end point is fixed in 7 (21%) patients with low and in 18 (12%) - with relatively high adherence (p=0.182). The number of angina attacks, having necessitated taking short-nitrate, decreased in the groups, respectively, with 5 (3; 10) and 6 (4; 10) to 2 (1; 3) per week (p=0.791). Thus, replacing generic trimetazidine with original trimetazidine MR in patients with a high frequency of angina attacks can achieve significant antianginal effect. Adherence of patients to the reception of the drug by an average 1/3 below the recommended amount does not affect the risk of emergency hospitalizations and/or ambulance calls for 16 weeks.

Leave-one-out procedure in the validation of elimination rate constant analysis.

Many registration agencies and other organizations define how to calculate the elimination rate constant (kel) value. No validation procedures have been introduced to verify the correct selection of the concentration-time (C-T) points used for the kel calculation. The purpose of this paper is to discover whether kel analysis can be subjected to the condensed validation procedure and what acceptance criteria should be adopted for such a procedure. For the analysis, data collected during bioequivalence studies of 4 drugs were selected, including 2 highly lipophilic drugs (itraconazole, atorvastatin) and 2 weakly lipophilic drugs (trimetazidine, perindopril). Pharmacokinetic calculations were performed with the use of WinNonlin Professional v 5.3. Internal validation of the kel analysis using leave-one-out cross-validation was performed. The present analysis proves that the C-T selection process for the kel calculations cannot be automated. In each of the analysed data series there were such C-T sequences that did not meet even one of the validation criteria. This paper proposes 3 validation criteria which need to be met in order to confirm the optimal selection of C-T data to calculate kel: Q 2≥0.6, R2≥ 0.85, Q 2-R2<0.3, were Q 2 - squared cross-validated correlation coefficient, R2 - coefficient of determination). Application of the validation procedure for the kel analysis under discussion proves the accuracy of the calculations, even if repeated kel analysis is based on a different sequence of points in the elimination phase.

[Pharmacokinetics and bioequivalence of domestic trimetazidine formulations].

OBJECTIVE: To compare the pharmacokinetics and bioequivalence between domestic hydrochloric trimetazidine capsules and imported hydrochloric trimetazidine tablets in healthy male Chinese volunteers after single oral administration. METHODS: A single oral dose (test and reference formulations) was given to 24 healthy male Chinese subjects according to an open randomized crossover design. The blood samples were collected before and after administration. Plasma trimetazidine concentration was determined by HPLC-MS/MS. The pharmacokinetic parameters were calculated by WinNonlin Ver 6.2.1 software. RESULTS: The main pharmacokinetic parameters of domestic and imported formulation of trimetazidine were similar: C(max) (70.9 ± 15.3), (66.4 ± 13.8) µg/ml; t(max) (1.70 ± 0.72), (1.85 ± 0.55) h; t(1/2z) (4.70 ± 1.75), (4.77 ± 1.96) h; AUC(0-24 h) (481 ± 176), (469 ± 171) µg×h×ml(-1); AUC(0-∞) (511 ± 189), (500 ± 188) µg×h×ml(-1). The estimated 90% CIs for the ratio of C(max) and AUC(0-24 h) were also similar: 101.9% - 112.5% and 99.4% - 104.9%. The relative bioavailability of domestic formulation was (102.2 ± 8.3)%. CONCLUSION: The results demonstrates that the domestic hydrochloric trimetazidine capsules and imported hydrochloric trimetazidine tablets are bioequivalent.

Food effect on bioavailability of modified-release trimetazidine tablets.

This study aimed to investigate a food effect on the bio-availability of modified-release (MR) trimetazidine tablets in 36 healthy volunteers. Trimetazidine, an anti-ischemic drug, protects the myocardial cell from the harmful effects of ischemia. The authors investigated the effect of being under a fasting or fed state at the time of drug intake on the bioavailability of trimetazidine 35-mg MR tablets in a randomized, open-label, crossover, 2-arm, 4-period, 2-sequence bioequivalence study design with a 14-day washout period. Plasma concentration of trimetazidine was assayed in timed samples with a validated high- performance liquid chromatography/mass selective detector that had a lower limit of quantification of 2.5 ng/mL. Test and reference formulations gave a mean trimetazidine C(max) of 63.26 ng/mL and 69.18 ng/mL for the fasting state and 64.19 ng/mL and 63.11 ng/mL for the fed state, respectively. The AUC(0-tlast) mean of trimetazidine was 726.31 ng·h/mL and 733.01 ng·h/mL for the fasting state and 706.40 ng·h/mL and 691.40 ng·h/mL for the fed state for test/reference formulations. There were no significant differences in pharmacokinetic parameters between the 2 formulations and the fasting/fed states. The authors showed that there is no food effect and no need for a 4-period study to evaluate the bioequivalence of trimetazidine MR tablets.

Relative bioavailability and pharmacokinetic study of two trimetazidine modified release formulations in healthy Bangladeshi male volunteers.

Trimetazidine (CAS 5011-34-7) is an effective and well-tolerated antianginal drug that possesses protective properties against ischemia-induced heart injury. The relative bioavailability and pharmacokinetic characteristics of two modified release formulations of 35 mg trimetazidine, one as the test product (Metacard MR) and one as the reference product, were compared in healthy Bangladeshi male volunteers. The randomized, two-way crossover study was conducted in 24 healthy male volunteers after administration of a single 35 mg dose of each modified release formulation after 12-h overnight fasting, with a washout period of two weeks. Blood samples were collected at various time intervals following oral administration and analyzed for trimetazidine concentrations using a validated HPLC method. The pharmacokinetic parameters were determined by a non-compartmental method. After administering a single dose of 35 mg of each trimetazidine formulation, the obtained mean (SD) values for the test and reference products were 104.78 (29.3) and 98.57 (28.7) ng/ml for Cmax; 4.00 (1.1) and 3.54 (1.32) h for t(max); 423.81 (173.9) and 410.01 (195.87) ng x h/ml for AUC0-12; and 472.51 (195.2) and 462.78 (225.13) ng x h/ml for AUC0-infinity respectively. The mean t1/2 was found 3.69 (1.1) h and 3.45 (0.72) h for test and reference products respectively. From paired t-test, no significant differences were observed (p > 0.05) for any pharmacokinetic parameters. The 90% confidence intervals of the test/reference mean ratios of the In-transformed AUC0-12, AUC0-infinity, and Cmax mean values were 106.19% (97.16%-116.06%), 104.74% (95.04%-115.42%) and 106.30% (95.23%-118.66%), respectively. The two formulations demonstrated similar bioavailability with respect to both the rate and extent of trimetazidine absorption.

A simple and sensitive liquid chromatography method for the determination of low dihydrocodeine concentrations in human plasma: its application in Chinese healthy volunteers.

A simple, sensitive and modified method was developed for determination of low dihydrocodeine (CAS 125-28-0) concentrations in human plasma by high performance-liquid chromatography (HPLC) with diode array detector. Measurement was performed on a Zorbax XDB-C18 analytical column together with a XDB-C18 precolumn at 40 degrees C after a simple one-step extraction. An isocratic mobile phase consisting of acetonitrile-0.1% trifluoroacetic acid (TFA)-water (12:40:48, v/v/v), was run at a flow rate of 1.0 mL/min. Good chromatographic separation was achieved in less than 6.2 min. This assay was linear over a concentration range of 2.50-100 ng/mL with a lower limit of quantification at 2.50 ng/mL. The intra- and inter-day precision (relative standard deviation) was less than 6.00 and 6.62%, respectively, at all concentration levels studied, while the intra- and inter-day accuracy was 1.50-3.73% and -1.35-1.92%, respectively. Recoveries were 76.10-83.81% with coefficients of variation of 1.86-6.93%. Stability of dihydrocodeine in plasma proved to be good. The validated method was successfully applied to a bioequivalence study of dihydrocodeine after a single oral administration of 20 mg dihydrocodeine tartrate in Chinese healthy male volunteers.

Floating tablet of trimetazidine dihydrochloride: an approach for extended release with zero-order kinetics.

Trimetazidine dihydrochloride is an effective anti-anginal agent; however, it is freely soluble in water and suffers from a relatively short half-life. To solve this encumbrance, it is a prospective candidate for fabricating trimetazidine extended-release formulations. Trimetazidine extended-release floating tablets were prepared using different hydrophilic matrix forming polymers including HPMC 4000 cps, carbopol 971P, polycarbophil, and guar gum. The tablets were fabricated by dry coating technique. In vitro evaluation of the prepared tablets was performed by the determination of the hardness, friability, content uniformity, and weight variation. The floating lag time and floating duration were also evaluated. Release profile of the prepared tablets was performed and analyzed. Furthermore, a stability study of the floating tablets was carried out at three different temperatures over 12 weeks. Finally, in vivo bioavailability study was done on human volunteers. All tablet formulas achieved < 0.5 min of floating lag time, more than 12 h of floating duration, and extended t (1/2). The drug release in all formulas followed zero-order kinetics. T4 and T8 tablets contained the least polymer concentration and complied with the dissolution requirements for controlled-release dosage forms. These two formulas were selected for further stability studies. T8 exhibited longer expiration date and was chosen for in vivo studies. T8 floating tablets showed an improvement in the drug bioavailability compared to immediate-release tablets (Vastrel® 20 mg).

Development and validation of a simple and sensitive liquid chromatography-tandem mass spectrometry method for quantifying trimetazidine in human plasma.

1. A simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS-MS) method for quantifying trimetazidine in human plasma was developed and validated. Sample preparation was based on deproteinating with acetonitrile. 2. Chromatography was performed on a C18 analytical column (5 mum; 150 x 2.1 mm i.d.) and the retention times for trimetazidine and cetirizine (used as the internal standard) were 1.8 and 3.0 min, respectively. The ionization was optimized using an electrospray ionization source and enhanced selectivity was achieved using tandem mass spectrometry. The calibration curve ranged from 0.1 to 200 ng/mL. The inter-day precision, accuracy and the relative standard deviation (RSD) were all < 15%. The analyte was shown to be stable over the time-scale of the entire procedure. 3. The robustness of the method was demonstrated by the good reproducibility of the results obtained during the analysis of clinical samples.

Liquid chromatography-tandem mass spectrometry method for the determination of trimetazidine in human plasma.

A sensitive liquid chromatography-tandem mass spectrometry (LC/MS/MS) method was developed and validated for the determination of trimetazidine (CAS 13171-25-0) in human plasma, using pseudoephedrine as internal standard (IS). Plasma samples were simply pretreated with methanol for deproteinization. The chromatographic separation was performed on a C18 column with a mobile phase of 3 mmol/L ammonium acetate solution-methanol (15:85, v/v) at a flow rate of 0.3 mL/min. The chromatographic separation was achieved in less than 3.2 min. The linearity was established over the concentration range of 1-100 ng/mL. Both intra- and inter-batch standard deviations were less than 9.5%. The method was successfully applied to study the relative bioavailability of trimetazidine hydrochloride tablets in healthy Chinese volunteers and the pharmacokinetic parameters of the reference and test tablets were compared.

Trimetazidine revisited: a comprehensive review of the pharmacological effects and analytical techniques for the determination of trimetazidine.

Trimetazidine (TMZ) is an effective and well-tolerated antianginal drug that possesses protective properties against ischemia-induced heart injury. Growing interest in metabolic modulation in recent years urged an up-to-date review of the literature on TMZ. This review consists of two major sections: (1) comprehensive and critical information about the pharmacological effects, mechanism of action, pharmacokinetics, side effects, and current usage of TMZ, and (2) developments in analytical techniques for the determination of the drug in raw material, pharmaceutical dosage forms, and biological samples.

Limonene enhances the in vitro and in vivo permeation of trimetazidine across a membrane-controlled transdermal therapeutic system.

The objective of the study was to design membrane-controlled transdermal therapeutic system (TTS) for trimetazidine. The optimization of (i) concentration of ethanol-water solvent system, (ii) HPMC concentration of drug reservoir and (iii) limonene concentration in 2% w/v HPMC gel was done based on the in vitro permeation of trimetazidine across excised rat epidermis. A limonene-based membrane-controlled TTS of trimetazidine was fabricated and evaluated for its in vivo drug release in rabbit model. The in vitro permeation of trimetazidine from water, ethanol and selected concentrations (25, 50 and 75% v/v) of ethanol-water co-solvent systems showed that 50% v/v of ethanol-water solvent system provided an optimal transdermal flux of 233.1+/-3.8 microg/cm(2.)h. The flux of the drug decreased to 194.1+/-7.4 microg/cm(2.)h on adding 2% w/v of HPMC to ethanolic (50% v/v ethanol-water) solution of trimetazidine. However, on adding selected concentrations of limonene (0, 2, 4, 6 and 8% w/v) to 2% w/v HPMC gel drug reservoir, the flux of the drug increased to 365.5+/-7.1 microg/cm(2.)h. Based on these results, 2% w/v HPMC gel drug reservoir containing 6% w/v of limonene was chosen as an optimal formulation for studying the influence of rate-controlling EVA2825 membrane and adhesive-coated EVA2825 membrane. The flux of the drug across EVA2825 membrane (mean thickness 31.2 microm) decreased to 285.8+/-2.2 microg/cm(2.)h indicating that the chosen membrane was effective as rate-controlling membrane. On applying an adhesive coat (mean thickness 10.2 microm) to EVA2825 membrane, the drug flux further decreased to 212.4+/-2.6 microg/cm(2.)h. However, the flux of the drug across adhesive-coated EVA2825 membrane-rat epidermis composite was 185.9+/-2.9 microg/cm(2.)h, which is about 2-times higher than the desired flux. The fabricated limonene-based TTS patch of trimetazidine showed a mean steady state plasma concentration of 71.5 ng/mL for about 14 h with minimal fluctuation when tested in rabbits. It was concluded from the investigation that the limonene-based TTS patch of trimetazidine provided constant drug delivery across the skin in rabbit model.

Transdermal permeation of trimetazidine from nerodilol-based HPMC gel drug reservoir system across rat epidermis.

OBJECTIVE: To study the in vitro transdermal permeation of trimetazidine from hydroxypropylmethyl cellulose (HPMC) gel drug reservoir system using nerodilol as a penetration enhancer. MATERIALS AND METHODS: An HPMC gel containing selected concentrations of nerodilol (0, 2, 4 or 5% w/v) and 2.5% w/v of trimetazidine was prepared, and subjected to in vitro permeation studies across rat epidermis. The amount of trimetazidine permeated at different time intervals (1, 2, 4, 8, 12, 18 and 24 h) was estimated, and the data were analyzed to calculate various permeation parameters. RESULTS: There was an increase in the amount of trimetazidine (8,719.7 +/- 153.3 microg/cm(2))permeated across the rat epidermis up to 24 h (Q(24)) with an increase in nerodilol concentration (5% w/v) in HPMC gel drug reservoir. However, no significant difference (p > 0.05) was observed in the amount of drug permeated (Q(24)) with 5% w/v of nerodilol when compared to that obtained with 4% w/v of nerodilol (8,484.5 +/- 165.8 microg/cm(2)). Nerodilol, at a concentration of 4% w/v enhanced the flux of trimetazidine across rat epidermis by about 1.96 times when compared to control. CONCLUSION: The HPMC gel drug reservoir containing 4% w/v of nerodilol showed optimal transdermal permeation of trimetazidine.

Sensitive and rapid LC-ESI-MS method for the determination of trimetazidine in human plasma.

A sensitive method, based on liquid chromatography-electrospray ionisation-mass spectrometry (LC-ESI-MS), was developed for the determination of trimetazidine in human plasma. Buflomedil was used as the internal standard (IS). Plasma samples were extracted with a mixture of cyclohexane-diethyl ether (1:1, v/v) and the analytes were chromatographically separated on a phenomenex Luna 5 mu C18 (2) 100A HPLC column with a mobile phase of 10 mM ammonium acetate buffer solution containing 0.1% acetic acid-methanol (45:55, v/v). The electrospray ionization was employed in a single quadrupole mass spectrometer for the analytical determination. The lower limit of quantification (LLOQ) was 0.5 ng/ml for trimetazidine and the measuring ranges were from 0.5 to 200 ng/ml. The intra- and inter-run standard deviation was less than 4.1% and 7.8%, respectively. The method was successfully applied to study the pharmacokinetics of trimetazidine in healthy Chinese volunteers.