FeS2 nanosheets-luminol-O2 chemiluminescence method for determination of venlafaxine hydrochloride, imipramine hydrochloride, and cefazolin sodium.

This study introduces a novel chemiluminescence (CL) approach utilizing FeS2 nanosheets (NSs) catalyzed luminol-O2 CL reaction for the measurement of three pharmaceuticals, namely venlafaxine hydrochloride (VFX), imipramine hydrochloride (IPM), and cefazolin sodium (CEF). The CL method involved the phenomenon of quenching induced by the pharmaceuticals in the CL reaction. To achieve the most quenching efficacy of the pharmaceuticals in the CL reaction, the concentrations of reactants comprising luminol, NaOH, and FeS2 NSs were optimized accordingly. The calibration curves demonstrated exceptional linearity within the concentration range spanning from 4.00 × 10-7 to 1.00 × 10-3 mol L-1, 1.00 × 10-7 to 1.00 × 10-4 mol L-1, and 4.00 × 10-6 to 2.00 × 10-4 mol L-1 with detection limits (3σ) of 3.54 × 10-7, 1.08 × 10-8, and 2.63 × 10-6 mol L-1 for VFX, IPM, and CEF, respectively. This study synthesized FeS2 NSs using a facile hydrothermal approach, and then the synthesized FeS2 NSs were subjected to a comprehensive characterization using a range of spectroscopic methods. The proposed CL method was effective in measuring the aforementioned pharmaceuticals in pharmaceutical formulations as well as different water samples. The mechanism of the CL system has been elucidated.

Molecular mechanism of EAG1 channel inhibition by imipramine binding to the PAS domain.

Ether-a-go-go (EAG) channels are key regulators of neuronal excitability and tumorigenesis. EAG channels contain an N-terminal Per-Arnt-Sim (PAS) domain that can regulate currents from EAG channels by binding small molecules. The molecular mechanism of this regulation is not clear. Using surface plasmon resonance and electrophysiology we show that a small molecule ligand imipramine can bind to the PAS domain of EAG1 channels and inhibit EAG1 currents via this binding. We further used a combination of molecular dynamics (MD) simulations, electrophysiology, and mutagenesis to investigate the molecular mechanism of EAG1 current inhibition by imipramine binding to the PAS domain. We found that Tyr71, located at the entrance to the PAS domain cavity, serves as a "gatekeeper" limiting access of imipramine to the cavity. MD simulations indicate that the hydrophobic electrostatic profile of the cavity facilitates imipramine binding and in silico mutations of hydrophobic cavity-lining residues to negatively charged glutamates decreased imipramine binding. Probing the PAS domain cavity-lining residues with site-directed mutagenesis, guided by MD simulations, identified D39 and R84 as residues essential for the EAG1 channel inhibition by imipramine binding to the PAS domain. Taken together, our study identified specific residues in the PAS domain that could increase or decrease EAG1 current inhibition by imipramine binding to the PAS domain. These findings should further the understanding of molecular mechanisms of EAG1 channel regulation by ligands and facilitate the development of therapeutic agents targeting these channels.

An Experimental and Theoretical Study of Laser Postionization of Femtosecond-Laser-Desorbed Drug Molecules.

Femtosecond laser desorption postionization mass spectrometry using 7.9 eV single-photon ionization (7.9 eV fs-LDPI-MS) detected three of four drug compounds previously found to have very low ionization efficiencies by secondary ion mass spectrometry. Electronic structure calculations of the ionization energies and other properties of these four drug compounds predicted that all display ionization energies below the 7.9 eV photon energy, as required for single-photon ionization. The 7.9 eV fs-LDPI-MS of carbamazepine, imipramine, and verapamil all showed significant precursor (M+) ion signal, but no representative signal was observed for ciprofloxacin. Furthermore, 7.9 eV fs-LDPI-MS displayed higher M+ signals and mostly similar fragment ions compared with 70 eV electron impact mass spectrometry. Ionization and fragmentation patterns are discussed in terms of calculated wave functions for the highest occupied molecular orbitals. The implications for improving lateral resolution and sensitivity of MS imaging of drug compounds are also considered.

Stimuli-responsive graphene-based hydrogel driven by disruption of triazine hydrophobic interactions.

The study reported here concerns the preparation of a novel graphene-diaminotriazine (G-DAT) nanocomposite hydrogel for application in the drug delivery field. The hybrid nature of this material is founded on two key elements: the presence of the DAT backbone induced the formation of hydrophobic regions that allowed efficient loading of a series of drugs of increasing hydrophobicity (Metronidazole, Benzocaine, Ibuprofen, Naproxen and Imipramine), while simultaneously endowing swelling-induced pH-responsiveness to the hydrogel. Additionally, the incorporation of graphene was found to interfere with these hydrophobic domains through favourable non-covalent interactions, thus leading to the partial disruption of these aggregates. As a consequence, graphene facilitated and enhanced the release of model hydrophobic drug Imipramine in a synergistic manner with the pH trigger, and increased the swelling capacities and improved mechanical performance. This hybrid hydrogel can therefore be envisaged as a proof-of-concept system for the release of hydrophobic compounds in the field of drug delivery.

The mechanism of a high-affinity allosteric inhibitor of the serotonin transporter.

The serotonin transporter (SERT) terminates serotonin signaling by rapid presynaptic reuptake. SERT activity is modulated by antidepressants, e.g., S-citalopram and imipramine, to alleviate symptoms of depression and anxiety. SERT crystal structures reveal two S-citalopram binding pockets in the central binding (S1) site and the extracellular vestibule (S2 site). In this study, our combined in vitro and in silico analysis indicates that the bound S-citalopram or imipramine in S1 is allosterically coupled to the ligand binding to S2 through altering protein conformations. Remarkably, SERT inhibitor Lu AF60097, the first high-affinity S2-ligand reported and characterized here, allosterically couples the ligand binding to S1 through a similar mechanism. The SERT inhibition by Lu AF60097 is demonstrated by the potentiated imipramine binding and increased hippocampal serotonin level in rats. Together, we reveal a S1-S2 coupling mechanism that will facilitate rational design of high-affinity SERT allosteric inhibitors.

Degradation of imipramine by vacuum ultraviolet (VUV) system: Influencing parameters, mechanisms, and variation of acute toxicity.

Degradation of imipramine (IMI) in the VUV system (VUV185 + UV254) was firstly evaluated in this study. Both HO• oxidation and UV254 direct photolysis accounted for IMI degradation. The quantum yields of UV254 direct photolysis of deprotonated and protonated IMI were 1.31×10-2 and 3.31×10-3, respectively, resulting in the higher degradation efficiency of IMI at basic condition. Increasing the initial IMI concentration lowered the degradation efficiency of IMI. While elevating reaction temperature significantly improved IMI degradation efficiency through the promotion of both the quantum yields of HO• and the UV254 direct photolysis rate. The apparent activation energy was calculated to be about 26.6 kJ mol-1. Negative-linear relationships between the kobs of IMI degradation and the concentrations of HCO3-/CO32-, NOM and Cl- were obtained. The degradation pathways were proposed that cleavage of side chain and hydroxylation of iminodibenzyl and methyl groups were considered as the initial steps for IMI degradation in the VUV system. Although some high toxic intermediate products would be produced, they can be further transformed to other lower toxic products. The good degradation efficiency of IMI under realistic water matrices further suggests that the VUV system would be a good method to degrade IMI in aquatic environment.

Toward Higher Sensitivity in Quantitative MALDI Imaging Mass Spectrometry of CNS Drugs Using a Nonpolar Matrix.

Tissue-specific ion suppression is an unavoidable matrix effect in MALDI mass spectrometry imaging (MALDI-MSI), the negative impact of which on precision and accuracy in quantitative MALDI-MSI can be reduced to some extent by applying isotope internal standards for normalization and matrix-matched calibration routines. The detection sensitivity still suffers, however, often resulting in significant loss of signal for the investigated analytes. An MSI application considerably affected by this phenomenon is the quantitative spatial analysis of central nervous system (CNS) drugs. Most of these drugs are low molecular weight, lipophilic compounds, which exhibit inefficient desorption and ionization during MALDI using conventional polar acidic matrices (CHCA, DHB). Here, we present the application of the (2-[(2 E)-3-(4- tert-butylphenyl)-2-methylprop-2-enylidene]malononitrile) matrix for high sensitivity imaging of CNS drugs in mouse brain sections. Since DCTB is usually described as an electron-transfer matrix, we provide a rationale (i.e., computational calculations of gas-phase proton affinity and ionization energy) for an additional proton-transfer ionization mechanism with this matrix. Furthermore, we compare the extent of signal suppression for five different CNS drugs when employing DCTB versus CHCA matrices. The results showed that the signal suppression was not only several times lower with DCTB than with CHCA but also depended on the specific tissue investigated. Finally, we present the application of DCTB and ultrahigh resolution Fourier transform ion cyclotron resonance mass spectrometry to quantitative MALDI imaging of the anesthetic drug xylazine in mouse brain sections based on a linear matrix-matched calibration curve. DCTB afforded up to 100-fold signal intensity improvement over CHCA when comparing representative single MSI pixels and >440-fold improvement for the averaged mass spectrum of the adjacent tissue sections.

Efficient degradation of imipramine by iron oxychloride-activated peroxymonosulfate process.

Synthesized iron oxychloride (FeOCl) was firstly applied to activate peroxymonosulfate (PMS) to degrade imipramine (IMI), a tricyclic antidepressant. Compared to some other Fe-based materials including zero valent iron, Fe2O3, Fe3O4 and ferric ions, FeOCl presented an impressive catalytic activity on PMS at near-neutral condition due to its unique structure containing abundant unsaturated iron atoms and oxo-bridged configuration. With an increase of FeOCl dose, PMS dose or initial pH in ranges of 0.02 - 0.5 g/L, 0.1 - 2.5 mM and 4.0 - 8.0, the degradation efficiency of IMI was effectively raised by 64.0%, 48.5% and 50.6%, respectively. The presence of either bicarbonate or chloride stimulated the removal of IMI. Moreover, 70.4% of IMI was degraded under the background of real water with 2 mM PMS. The possible reactive species were identified as sulfate and hydroxyl radicals. The formed hypochlorite through the reaction of PMS and the released chloride ions may also contribute to the degradation of IMI. Among the oxidants, sulfate radical was proven to be the dominate one in the system. Additionally, the FeOCl/PMS system can overall effectively degrade six other organic compounds including amitriptyline, desipramine, propranolol, nitrobenzene, methyl-paraben and ethyl-paraben, further suggesting the possible application of this system in treatment of vast aquatic micro-organic pollutants.

Super paramagnetic core-shells anchored onto silica grafted with C8/NH2 nano-particles for ultrasound-assisted magnetic solid phase extraction of imipramine and desipramine from plasma.

In current work the Fe3O4 magnetic nano-particles anchored to core-shells of SiO2 which grafted by C8/NH2 dual mixed groups, have been synthesized. The magnetic nano-particles were characterized by scanning electron microscopy, X-ray diffraction spectroscopy, and zeta-potential reader. The resulted nano-particles have spherical structure with diameters in the range of 105 to 110 nm. A magnetic solid phase extraction method was developed for extraction of imipramine and desipramine from human plasma samples under ultrasonic conditions by using of prepared NPs as sorbent. The MNPs were dispersion in plasma under sonicated conditions, accumulated by an external magnetic field and washed with Briton-Robinson buffer-acetonitrile solution (0.05 mol l-1, pH = 5, 10%V/V). The drugs were removed by methanol and quantified by gas chromatography. The calibration curves (correlation coefficient > 0.99) for IMP and DES were linear in the concentration range of 0.005 to 5 and 0.01 to 4 µg ml-1, respectively. The LOD, LOQ, intra and inter-day precision values were measured too. The proposed Fe3O4/SiO2/C8/NH2 MNPs could be applied for 3.0 times.

Inhibition of acid sphingomyelinase disrupts LYNUS signaling and triggers autophagy.

Activation of the lysosomal ceramide-producing enzyme, acid sphingomyelinase (ASM), by various stresses is centrally involved in cell death and has been implicated in autophagy. We set out to investigate the role of the baseline ASM activity in maintaining physiological functions of lysosomes, focusing on the lysosomal nutrient-sensing complex (LYNUS), a lysosomal membrane-anchored multiprotein complex that includes mammalian target of rapamycin (mTOR) and transcription factor EB (TFEB). ASM inhibition with imipramine or sphingomyelin phosphodiesterase 1 (SMPD1) siRNA in human lung cells, or by transgenic Smpd1+/- haploinsufficiency of mouse lungs, markedly reduced mTOR- and P70-S6 kinase (Thr 389)-phosphorylation and modified TFEB in a pattern consistent with its activation. Inhibition of baseline ASM activity significantly increased autophagy with preserved degradative potential. Pulse labeling of sphingolipid metabolites revealed that ASM inhibition markedly decreased sphingosine (Sph) and Sph-1-phosphate (S1P) levels at the level of ceramide hydrolysis. These findings suggest that ASM functions to maintain physiological mTOR signaling and inhibit autophagy and implicate Sph and/or S1P in the control of lysosomal function.

Chromatographic studies of drug interactions with alpha1-acid glycoprotein by ultrafast affinity extraction and peak profiling.

Interactions with serum proteins such as alpha1-acid glycoprotein (AGP) can have a significant effect on the behavior and pharmacokinetics of drugs. Ultrafast affinity extraction and peak profiling were used with AGP microcolumns to examine these processes for several model drugs (i.e., chlorpromazine, disopyramide, imipramine, lidocaine, propranolol and verapamil). The association equilibrium constants measured for these drugs with soluble AGP by ultrafast affinity extraction were in the general range of 104-106M-1 at pH 7.4 and 37°C and gave good agreement with literature values. Some of these values were dependent on the relative drug and protein concentrations that were present when using a single-site binding model; these results suggested a more complex mixed-mode interaction was actually present, which was also then used to analyze the data. The apparent dissociation rate constants that were obtained by ultrafast affinity extraction when using a single-site model varied from 0.14 to 7.0s-1 and were dependent on the relative drug and protein concentrations. Lower apparent dissociation rate constants were obtained by this approach as the relative amount of drug versus protein was decreased, with the results approaching those measured by peak profiling at low drug concentrations. This information should be useful in better understanding how these and other drugs interact with AGP in the circulation. In addition, the chromatographic approaches that were optimized and used in this report to examine these systems can be adapted for the analysis of other solute-protein interactions of biomedical interest.

The capacity and effectiveness of diosmectite and charcoal in trapping the compounds causing the most frequent intoxications in acute medicine: A comparative study.

The aim of the study was to compare the adsorption ability of two adsorbent materials, namely diosmectite and activated charcoal towards selected model compounds that are most commonly involved in acute intoxication. Eleven model compounds were selected: acetylsalicylic acid, α-amanitin, amlodipine, digoxin, phenobarbital, ibuprofen, imipramine, carbamazepine, oxazepam, promethazine, and theophylline. Of the tested compounds, promethazine and imipramine were the most effectively adsorbed to diosmectite. Their adsorption to diosmectite (0.356±0.029mg promethazine/mg diosmectite and 0.354±0.019mg imipramine/mg diosmectite, respectively) was significantly higher than their adsorption to activated charcoal. The effect of temperature and pH on the adsorption efficiencies was also evaluated. In the case of experiments with mixture of both adsorbents, they mostly behaved in a solution independently or in a slightly antagonistic way. Using various methods such as N2 adsorption and thermogravimetric analysis, the structure and texture of diosmectite and activated charcoal were attained.

Serotonergic and dopaminergic systems are implicated in antidepressant-like effects of chotosan, a Kampo formula, in mice.

We previously demonstrated that chotosan (CTS), a traditional herbal formula called Kampo medicine, improves diabetes-induced cognitive deficits. In the present study, we investigated the antidepressant-like effects of CTS in mice. The administration of CTS (1.0 g/kg, for 3 days) decreased the immobility time in the forced-swim test, and this decrease was prevented by the prior administration of sulpiride (an antagonist of D2/3 receptors) and WAY100635 (an antagonist of 5-HT1A receptors). None of the treatments tested altered the locomotor activity of mice. These results suggest that CTS exerts antidepressant-like effects through changes in the serotonergic and dopaminergic systems.

High-throughput virtual screening and quantum mechanics approach to develop imipramine analogues as leads against trypanothione reductase of leishmania.

Visceral leishmaniasis (VL) has been considered as one of the most fatal form of leishmaniasis which affects 70 countries worldwide. Increased drug resistance in Indian subcontinent urged the need of new antileishmanial compounds with high efficacy and negligible toxicity. Imipramine compounds have shown impressive antileishmanial activity. To find out most potent analogue from imipramine series and explore the inhibitory activity of imipramine, we docked imipramine analogues (n=93,328) against trypanothione reductase in three sequential modes. Furthermore, 98 ligands having better docking score than reference ligand were subjected to ADME and toxicity, binding energy calculation and docking validation. Finally, Molecular dynamic and single point energy was estimated for best two ligands. This study uncovers the inhibitory activity of imipramine against Leishmania parasites.

Membrane anchor of cytochrome P450 reductase suppresses the uncoupling of cytochrome P450.

Cytochrome P450 reductase (CPR) is an important redox partner of microsomal CYPs. CPR is composed of a membrane anchor and a catalytic domain that contains FAD and flavin mononucleotide (FMN) as redox centers and mediates electron transfer to CYP. Although the CPR membrane anchor is believed to be requisite for interaction with CYP, its physiological role is still controversial. To clarify the role of the anchor, we constructed a mutant (Δ60-CPR) in which the N-terminal membrane anchor was truncated, and studied its effect on binding properties, electron transfer to CYP2C19, and drug metabolism. We found that Δ60-CPR could bind to and transfer electrons to CYP2C19 as efficiently as WT-CPR, even in the absence of lipid membrane. In accordance with this, Δ60-CPR could mediate metabolism of amitriptyline (AMT) and imipramine (IMP) in the absence of lipids, although activity was diminished. However, Δ60-CPR failed to metabolize omeprazole (OPZ) and lansoprazole (LPZ). To clarify the reason for this discrepancy in drug metabolism, we investigated the uncoupling reaction of the CYP catalytic cycle. By measuring the amount of H2O2 by-product, we found that shunt pathways were markedly activated in the presence of OPZ/LPZ in the Δ60-CPR mutant. Because H2O2 levels varied among the drugs, we conclude that the proton network in the distal pocket of CYP2C19 is perturbed differently by different drugs, and activated oxygen is degraded to become H2O2. Therefore, we propose a novel role for the membrane anchor as a suppressor of the uncoupling reaction in drug metabolism by CYP.

Rapid LC-MS/MS method for determination of drotaverine in a bioequivalence study.

A liquid chromatography coupled with tandem mass spectrometry method for the quantification of the antispasmodic drug drotaverine in human plasma was developed and validated according to the current bioanalytical guidelines. The internal standard used was imipramine. The separation was performed on a Kinetex C18 50×3mm, 2.6µm column under isocratic conditions using a mobile phase of 65:35 (v/v) formic acid 0.2% (v/v) in water and acetonitrile at 40°C with a flow rate of 0.4ml/min. The detection of drotaverine and the internal standard was performed in multiple reaction monitoring (MRM) mode using an ion trap mass spectrometer with electrospray ionization, operating in positive mode. The human plasma samples (0.24ml) were deproteinized with methanol and aliquots of 4µl from supernatants obtained after centrifugation were directly injected into the chromatographic system. The method shows a good linearity (r(2)>0.997), precision (CV<6.3%) and accuracy (bias<5.4%) over the range of 2.24-448ng/ml drotaverine in plasma. The recovery was between 91 and 98%. The limit of quantification was 2.24ng/ml. The analysis required only a 3.0min run. The developed and validated method for the determination of drotaverine in human plasma was successfully applied in a bioequivalence study, for analyzing approximately 1000 subject's samples.

Comparative release studies of two cationic model drugs from different cellulose nanocrystal derivatives.

Native cellulose nanocrystal (CNC), oxidized CNC (CNC-OX) and chitosan oligosaccharide grafted CNC (CNC-CSOS) were evaluated as potential drug delivery carriers for two model drug compounds, procaine hydrochloride (PrHy) and imipramine hydrochloride (IMI). The loading of PrHy and IMI was performed at pH 8 and 7, respectively. IMI displayed higher binding to CNC derivatives than PrHy. Drug selective membranes were prepared for each model drug and a drug selective electrode system was used to measure the drug concentration in the filtrate and release medium. Isothermal Titration Calorimetry (ITC) was used to elucidate the types of interactions between model drugs and CNC and its derivatives. The complexation between model drugs and CNC derivatives was confirmed by zeta potential and transmittance measurements. The binding and release of these drugs correlated with the nature and types of interactions that exist between the CNC and drug molecules.

N-demethylation and N-oxidation of imipramine in rat thoracic aortic endothelial cells.

The aim of this study was to examine whether cultured rat thoracic aortic endothelial cells (TAECs) have the ability to metabolize the tertiary amine, imipramine. In rat TAECs, imipramine was biotransformed into N-demethylate and N-oxide by cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO), respectively. The intrinsic clearance (V max/K m) for the N-oxide formation was approximately five times as high as that for the N-demethylate formation, indicating that oxidation by CYP was much higher than that by FMO. Moreover, we suggest that CYP2C11 and CYP3A2 are key players in the metabolism to N-demethylate in rat TAECs using the respective anti-rat CYP antibodies (anti-CYP2C11 and anti-CYP3A2). The presence of CYP2C11 and CYP3A2 proteins was also confirmed in cultured rat TAECs using a polyclonal anti-CYP antibody and immunofluorescence microscopy. In contrast, the formation rate of N-oxide at pH 8.4 was higher than that at pH 7.4. Inhibition of N-oxide formation by methimazole was found to be the best model of competitive inhibition yielding an apparent K i value of 0.80 µmol/L, demonstrating that N-oxidation was catalyzed by FMO in rat TAECs. These results suggest that rat TAEC enzymes can convert substrates of exogenous origin such as imipramine, indicating that TAECs have an important function for metabolic products, besides hepatic cells.

In silico study on the inhibitory interaction of drugs with wild-type CYP2D6.1 and the natural variant CYP2D6.17.

The natural variant of the cytochrome P450 enzyme CYP2D6.1, CYP2D6.17, is most common in African populations, has three amino acid substitutions (T107I, R296C, and S486T) compared to the wild-type, and is known to have a different ligand preference from CYP2D6.1. It is becoming increasingly important to understand differences in the metabolism of medicines in different ethnic groups in order to assess the relevance of clinical data from different countries. This study investigated differences in the inhibition profiles of drugs for CYP2D6 with respect to gene polymorphisms. Firstly, we used computer docking with six drugs to several CYP2D6.1 structures, sampled from the trajectory of MD simulations, and calculated MM-GB/SA scores representing binding free energies. We then used regression analysis to predict the potency with which drugs inhibited CYP2D6.1 based on MM-GB/SA scores. The pKi-values obtained were in good agreement with experimental values measured for the six drugs (r(2) = 0.81). We carried out the same analysis for CYP2D6.17 and the pKi-values calculated were also in good agreement with experimental values (r(2) = 0.92). Finally, we were able to successfully explain the different abilities of CYP2D6.1 and CYP2D6.17 to metabolize drugs in different ethnic groups with reference to their 3D-structures.

[Production and assessing release of imipramine and magnesium from tablets]. / Technologia otrzymywania i ocena uwalniania imipraminy i magnezu z tabletek.

BACKGROUND: In the pharmaceutical technology there is a trend to produce tablets composed of several medicinal substances to increase therapeutic effect and reduce the frequency of drug administration. In the literature there are reports concerning pharmacological studies in which a potentiation of the effects has been observed after a co-administration of antidepressant imipramine and magnesium. Currently, there is no formulation on the market comprising imipramine and magnesium, therefore, it was decided to produce uncoated tablets. In order to prepare the tablets by direct compression, it was necessary to select suitable excipients. OBJECTIVES: The aim of the study was to elaborate the composition and to prepare the tablets with imipramine and magnesium, as well as to assess the quality of the tablets by physical characteristics and by the release study of the active substances. MATERIAL AND METHODS: In order to prepare the tablets, compositions of different polymers and other excipients were added. The tablets were produced by direct compression method in a tablet press. Physical properties of the obtained tablets and the release of the active substances into an acidic medium in a paddle apparatus were tested. The contents of imipramine and magnesium were determined by different methods: spectrophotometrically and atomic absorption spectrometry, respectively. RESULTS: The composition of excipients necessary to produce tablets comprising imipramine and magnesium was established. All of prepared tablets were in compliance with the pharmacopoeial requirements. The release tests showed that above 80% of imipramine was released within 20-35 min and 80-76% of magnesium up to 45 min from the composed tablets and one-ingredient tablets, respectively. CONCLUSIONS: The compositions of excipients for tablets consisting of imipramine and magnesium were presented. The active substances were released within 45 min in the acidic medium, and the administration of these substances in the composed tablets did not affect pharmaceutical availability.