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Purpose: This study compares the pharmacokinetic and safety profiles between a new generic and a branded reference formulation of amitriptyline hydrochloride tablets, and assesses the bioequivalence of the two products in healthy Chinese volunteers to obtain sufficient evidence for the marketing approval of the generic drug., Materials and Methods: A randomized, open-label, two-period crossover study (clinicaltrials.gov, NCT03646526) was conducted under both fasting and fed conditions in healthy Chinese volunteers (24 subjects/condition). Eligible subjects randomly received a single 25 mg dose of either the test or the reference formulation, followed by a 3-week washout period. Blood samples were collected until 144 h following administration. The pharmacokinetic parameters were acquired based on the concentration-time profiles, including the areas under the plasma concentration-time curve (AUC 0-t , AUC 0-∞ ), the peak plasma concentration (C max ), the time to achieve C max (T max ), and the elimination half-life (t 1/2 ). The geometric mean ratios (GMRs) and the corresponding 90% confidence intervals (CIs) of amitriptyline were acquired for bioequivalence analysis, and values of these parameters for nortriptyline were used for comparison of therapeutic outcomes. Safety assessments included laboratory tests, physical examination, vital signs, and incidence of adverse events (AEs)., Results: The values of t 1/2 and T max for amitriptyline were not significantly different between the test and reference products under both fasting and fed conditions (P > 0.05). The GMRs of C max , AUC 0-t , and AUC 0-∞ between the two products, and corresponding 90% CIs, were all within the range of 80% to 125% under both fasting and fed conditions. The test and reference products were well tolerated and did not elicit serious adverse events., Conclusion: This study demonstrated that the generic and reference products were well tolerated by the subjects and bioequivalent, according to the rate and extent of the drug absorption., Competing Interests: Hunan Dongting Pharmaceutical Co., Ltd. (Hunan, China) funded our study, which was the manufacturer of amitriptyline hydrochloride tablets. The funder had not any influence on data collection and analysis, manuscript preparation, and decision to publish. All authors report no conflicts of interest in this work., (© 2020 Zhai et al.)

Aim: To investigate the enhancement of bioavailability by the usage of drug nanoparticles for increasing the efficacy of antidepressant therapeutic value. Materials & methods: Nano-amitriptyline HCI (AMT·HCl) particles were successfully prepared via a simple spray freeze drying (SFD) method. Results: The as-prepared nanoparticles are amorphous instead of crystalline. The mean size of AMT·HCl nanoparticles is 90 nm. In in vitro evaluation, AMT·HCl nanoparticles have greatly improved the dissolution compared with pure bulk materials, which have potential for enhancing human bioavailability and diminishing toxic effect. A nanoparticle formation mechanism was also proposed. Conclusion: These findings promote the development of antidepressant therapeutic evaluation based on the usage of AMT·HCl nanoparticles by SFD method and indicate that SFD is an alternative for a range of nanoparticle preparation in industrial pharmacy.

The removal of three emerging contaminants (ECs) (amitriptyline hydrochloride (AH), methyl salicylate (MS) and 2-phenoxyethanol (PE)) dissolved in several water matrices by means of their adsorption onto powdered activated carbon (PAC) and granular activated carbon (GAC) has been investigated. When dissolved in ultrapure water, adsorption of the ECs followed the trend of AH > MS > PE, with a positive effect of the adsorbent dose. According to the analysis of the adsorption isotherms and adsorption kinetics, PAC showed strongly higher adsorption efficiency in both capacity and velocity of the adsorption, in agreement with its higher mesoporosity. Equilibrium isotherm data were fitted by Langmuir and Freundlich models. Pseudo-second order kinetics modeled very successfully the adsorption process. Finally, the effect of the presence of dissolved organic matter (DOM) in the water matrices (ultrapure water, surface water and two effluents from wastewater treatment plants) on the adsorption of the selected ECs onto PAC was established, as well as its performance on the removal of water quality parameters. Results show a negative effect of the DOM content on the adsorption efficiency. Over 50% of organic matter was removed with high PAC doses, revealing that adsorption onto PAC is an effective technology to remove both micro-pollutants and DOM from water matrices.

Herein, we have explored the interaction between amitriptyline hydrochloride (AMT) and hemoglobin (Hb), using steady-state and time-resolved fluorescence spectroscopy, UV-visible spectroscopy, and circular dichroism spectroscopy, in combination with molecular docking and molecular dynamic (MD) simulation methods. The steady-state fluorescence reveals the static quenching mechanism in the interaction system, which was further confirmed by UV-visible and time-resolved fluorescence spectroscopy. The binding constant, number of binding sites, and thermodynamic parameters viz. ΔG, ΔH, ΔS are also considered; result confirms that the binding of the AMT with Hb is a spontaneous process, involving hydrogen bonding and van der Waals interactions with a single binding site, as also confirmed by molecular docking study. Synchronous fluorescence, CD data, and MD simulation results contribute toward understanding the effect of AMT on Hb to interpret the conformational change in Hb upon binding in aqueous solution.

Purpose: Amitriptyline is the most widely used tricyclic antidepressant (TCA). Although amitriptyline hydrochloride 10 and 25 mg has been marketed in Korea, no data on the dose proportionality of amitriptyline in Korean subjects are available. This clinical trial was designed to evaluate and compare the relative bioavailability with regard to dose proportionality between the two marketed strengths of amitriptyline hydrochloride tablets after a single-dose, oral administration under fasting conditions in healthy, male, Korean volunteers., Methods: This single-dose, randomized, open-label, 2-way crossover study was conducted in healthy male Korean subjects. Subjects were randomly assigned to 1 of 2 dose groups and received a single dose of 10 or 25 mg amitriptyline hydrochloride under fasting conditions, followed by the alternate dose in the subsequent study period. High performance liquid chromatography (HPLC)-mass spectrometry (MS)/MS detection was applied to determine plasma concentrations. Pharmacokinetic parameters were calculated, C(max), AUC(last), AUC(0-∞), t(½), and T(max). Statistical analysis was performed for the assessment of dose proportionality. Tolerability was assessed for up to 96 hours after administration., Findings: Twelve healthy Korean subjects completed this trial (mean [SD] age, 21.7 [1.9] years; height, 174.5 [5.0] cm; and weight, 66.7 [9.4] kg). Although 4 subjects experienced a total 5 adverse events (AEs), no serious AEs were reported during the study. The mean values of C(max) and AUC were proportional to the doses of 10 and 25 mg. The C(max), AUC(last), and AUC(0-∞) of amitriptyline hydrochloride 10 mg were 5.96 ng/mL, 91.35 ng·h/mL and 109.74 ng·h/mL, respectively. The C(max), AUC(last), and AUC(0-∞) of amitriptyline hydrochloride 25 mg were 17.69 ng/mL, 260.68 ng·h/mL, and 296.87 ng·h/mL, respectively., Implications: Our results suggest that the 2 strengths of amitriptyline hydrochloride (10 and 25 mg) exhibited linear (dose-dependent) pharmacokinetics in these healthy, male, Korean subjects. Based on these results, a predictable and linear increase in systemic exposure can be expected. ClinicalTrials.gov identifier: NCT01367080., (Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.)

A simple CE method was developed and validated for the simultaneous determination of chlordiazepoxide (CHL), amitriptyline, and nortriptyline (mixture I) or the determination of CHL and imipramine (mixture II) using the same BGE. Sertraline and amitriptyline were used as internal standards for the first and second mixtures, respectively. The method allows amitriptyline to be completely separated from its impurity and main metabolite nortriptyline, which can be quantified from 0.2 μg/mL. The separation was achieved using 20 mM potassium phosphate buffer pH 5 containing 12 mM β-cyclodextrin and 1 mM carboxymethyl-β-cyclodextrin. UV detection was performed at 200 nm and a voltage of 15 kV was applied on an uncoated fused-silica capillary at 25°C. These experimental conditions allowed separation of the compounds to be obtained in 7 min. Calibration graphs proved the linearity up to 40 μg/mL for CHL, up to 100 μg/mL for amitriptyline and imipramine, and up to 5 μg/mL for nortriptyline. The accuracy and precision of the method have been determined by analyzing synthetic mixtures and pharmaceutical formulations. The analytical results were quite good in all cases indicating that the method was linear, sensitive, precise, accurate, and selective for both mixtures., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: The purpose of this study was to develop a novel and continuous method for preparing a nanosized particle of drug crystals and to characterize its properties., Materials and Methods: A new apparatus was introduced to crystallize nanosized drug crystals of amitriptyline hydrochloride as a model drug. The samples were prepared in the pure state by ultrasonic spray, and elaborated deposition was completed via electrostatic adsorption. Scanning electron microscopy, X-ray powder diffraction, and atomic force microscopy were used to characterize the size of the particles; this was subsequently followed by differential scanning calorimetry., Results and Discussion: Nanoparticles of drug crystals were successfully prepared. The size of the drug crystals ranged from 20 nm to 400 nm; the particle size of amitriptyline hydrochloride was approximately 71 nm. The particles were spherical and rectangular in shape. Moreover, the melting point of the nanoparticles decreased from 198.2°C to 196.3°C when compared to raw particle crystals. Furthermore, the agglomeration effect was also attenuated as a result of electrostatic repulsion among each particle when absorbed, and depositing on the inner wall of the gathering unit occurred under the electrostatic effect., Conclusion: Ultrasonic spray-assisted electrostatic adsorption is a very effective and continuous method to produce drug nanocrystals. This method can be applied to poorly water-soluble drugs, and it can also be a very effective alternative for industrial production. Once the working parameters are given, drug nanocrystals will be produced continuously.

The antidepressant drug amitriptyline hydrochloride was obtained in a dry powder form and was screened against 253 strains of bacteria which included 72 Gram positive and 181 Gram negative bacteria and against 5 fungal strains. The minimum inhibitory concentration (MIC) was determined by inoculating a loopful of an overnight peptone water culture of the organism on nutrient agar plates containing increasing concentrations of amitriptyline hydrochloride (0, 10 μg/mL, 25 μg/mL, 50 μg/mL, 100 μg/mL, 200 μg/mL). Amitriptyline hydrochloride exhibited significant action against both Gram positive and Gram negative bacteria at 25-200 μg/mL. In the in vivo studies it was seen that amitriptyline hydrochloride at a concentration of 25 μg/g and 30 μg/g body weight of mouse offered significant protection to Swiss strain of white mice when challenged with 50 median lethal dose (MLD) of a virulent strain of Salmonella typhimurium NCTC 74. The in vivo data were highly significant (p<0.001) according to the chi-square test.