Telmisartan Research Articles

Supersaturable self-microemulsifying drug delivery system enhances dissolution and bioavailability of telmisartan

To enhance the dissolution and oral bioavailability of telmisartan (TMS), a poorly water-soluble anti-hypertensive drug, a supersaturable self-microemulsifying drug delivery system (SuSMEDDS) was developed. Amorphous alkalinized TMS (AAT) was formulated into a SMEDDS, composed of Capmul® MCM (oil), Cremophor® RH40 (surfactant), and tetraglycol (co-surfactant). Although the SMEDDS was rapidly dissolved (>80% within 5 min) in a limited condition (500 mL, pH 6.8), drug precipitation was observed over time, resulting in a decrease in dissolution levels. The precipitation was due to drug recrystallization, as determined by differential scanning calorimetry and powder X-ray diffraction analyses. Several polymers, including Soluplus® (SOL), were screened as precipitation inhibitors; ultimately, SuSMEDDS-SOL was prepared by admixing SOL and the SMEDDS at a 5:100 (w/w) ratio. SuSMEDDS-SOL was superior in terms of dissolution efficiency (>90% over 2 h) and dissolution-retaining time (no precipitation over 2 h). An in vivo pharmacokinetic study in rats revealed that the oral bioavailability of SuSMEDDS-SOL was 4.8-, 1.3-, and 1.2-fold greater than those of the TMS suspension, AAT solution, and SMEDDS, respectively. Therefore, SuSMEDDS-SOL is a promising candidate to enhance the dissolution and oral bioavailability of TMS.

Trade-off efficacy and data processing strategy in the power of spectral resolution of co-formulated antihypertensive pharmaceuticals.

Versatile, extraction-free univariate spectrophotometric methods have been modified to get effective spectral resolution of mixtures in accordance with their feature challenges. The proposed methods have been applied and validated for analyzing some antihypertensive medicines in their co-formulated medicinal products. Two mixtures have been used: the first one [Mix I (OLM/ADB)] is composed of Olmesartan medoxomil (OLM) and Amlodipine besylate (ADB) with partly-overlapped spectra while the second [Mix II (TEL/HCT)] is made up Telmisartan (TEL) and Hydrochlorothiazide (HCT) with total-overlapped spectra. Induced dual wavelength, absorbance correction and ratio subtraction coupled with constant multiplication methods were applied to Mix I (OLM/ADB), while dual wavelength, advanced absorbance subtraction and constant center coupled with spectrum subtraction methods were applied to Mix II (TEL/HCT). Calibration graphs were established with good correlation coefficients. The methods exhibit significant advantages as simplicity, sensitivity, minimal data manipulation besides optimum robustness. Selectivity was inspected using lab-mixtures with diverse ratios. Accuracy, precision and repeatability were found to be within the acceptable limits. The proposed methods are good enough to be used for co-assay of analytes in combined forms without any interfering from excipients. Moreover, all results were estimated in accordance with ICH criteria and successfully compared with those of the reported methods applying t-test and F-test at 95% confidence level. Generally, these methods can be used efficiently for routine quality control testing.

Facile separation of four co-formulated ternary antihypertensive drug combinations with a customized elution protocol using supercritical fluid chromatography

A novel supercritical fluid chromatography (SFC) method is described to analyze four antihypertensive drug combinations containing a diuretic (hydrochlorothiazide, HCT), a calcium channel blocker (amlodipine, AML) and an angiotensin receptor blocker (olmesartan (OLM)/ telmisartan (TEL)/valsartan (VAL)/renin inhibitor (aliskiren, ALI) using a customized protocol. The effect of mobile phase, analytical column, temperature and pressure were suitably optimized. The best conditions for separation was achieved on DCPak P4VP (250 × 4.6 mm, 5 µm) column using CO2 and 0.1% formic acid in methanol by gradient elution for all drug combinations. The chromatographic separations were accomplished within 5.0 min at 125 bar back pressure and 40 °C column temperature. Detection and quantitation of analytes was performed at 230 and 250 nm using a photo diode array detector. The resolution factor Rs between the drugs ranged from 1.52 to 3.85 for different combinations. The study showed decrease in retention factors (k) of the drugs with increase in temperature and pressure. The van’t Hoff plots revealed enthalpy driven process for the separation of all drug combinations. The method was validated as per ICH guidelines for specificity, sensitivity, accuracy and precision and recovery. Method linearity was established from 10.0–300, 1.0–20/25, 2.00–100, 5.00–200, 2.00–100 and 5.00–200 µg/mL for ALI, AML, HCT, OLM, TEL and VAL, respectively. Application of the method was demonstrated by analyzing single pill combinations of ALI–AML–HCT, OLM–AML–HCT, TEL–AML–HCT and VAL–AML–HCT. The significance of the method for accuracy and precision was assessed using Student’s t-test and F-test.

Formulation and In Vitro Evaluation of Telmisartan Nanoparticles Prepared by Emulsion-Solvent Evaporation Technique.

Telmisartan (TLM) is an antihypertensive drug that has been shown to have antiproliferative effects on cancer cells. It has low solubility and suboptimal oral bioavailability. To investigate the potential anticancer effect of TLM on breast cancer cells, poly (D, L-lactide) (PLA) nanoparticles were formulated with the benefit of improving its solubility. TLM-loaded PLA nanoparticles were prepared by emulsion solvent evaporation. The effects of sonication time and polymer:drug ratio on nanoparticle size and drug encapsulation were investigated. TLM-loaded nanoparticles were tested against MCF-7 and MD-AMB-231 breast cancer cell lines for antiproliferative effects. Nanoparticles with mean particle size 272 nm and 79% encapsulation efficiency were obtained. Sustained release TLM nanoparticles (40% in 24 h) decreased cell viability to 45% for MCF-7 cells at 72 h, even at the lowest TLM concentration, indicating better anticancer efficiency than TLM solution. TLM nanoparticles could be potential anticancer agents for breast cancer and deserve further studies.

Telmisartan detection by UV spectrophotometry in mice drinking water.

Animal models are often used to test the safety and efficacy of drugs in cell culture and body systems. Several researchers deliver drugs to rodents in drinking water, although it has some limitations. For instance, drug stability, water consumption, and body mass fluctuation may change drug dose. Thus, we investigated telmisartan (TEL) stability in mice drinking water by UV spectrophotometry, and if water intake and body mass were fluctuated then it changes the predicted drug dose. The results showed that UV spectrophotometry could detect TEL at the wavelength of 300nm, and the concentration curve was set between 1.25 and 60µg/mL. Also, it remained stable in mice drinking water for 7 days at the predicted concentration. Mice gained weight after 8 weeks on a high-fat high-sucrose diet, and it was reduced by TEL 5mg/kg/day after 3 weeks. Although water intake remained stable, not adjusting the TEL concentration weekly by body mass would lead to higher consumption of TEL by mice. In conclusion, we demonstrated that body mass and water intake fluctuations significantly change the amount of drug that the animal receives, which would add bias to the experiment. TEL remains stable for at least 7 days in wrapped mice water bottles in the animal care facility, and UV spectrophotometry proved to be a simple and low-cost method to detect TEL in mice drinking water.

Chitosan coated magnetic nanoparticles as carriers of anticancer drug Telmisartan: pH-responsive controlled drug release and cytotoxicity studies

Chitosan, a natural, hydrophilic and biodegradable polymer was grafted on Fe3O4 magnetic nanoparticles (MNPs) and used as a carrier of poorly water-soluble anticancer drug Telmisartan (TEL). The characteristics of MNPs and chitosan coated MNPs (MNP-CS) were determined by using X-ray diffraction, field emission scanning electron microscope, transmission electron microscope, vibrating sample magnetometer, and BET surface area analyzer. The chitosan coating of MNPs was validated by Fourier transform infrared spectroscopy (FTIR) and thermal gravimetric analysis. The drug was loaded on MNP-CS through an amide bond between amino groups of chitosan and carboxylic groups of TEL. The drug loading capacity of ~50% was obtained due to the large BET surface area (134 m2/g) of mesoporous MNP-CS. Drug loaded MNP-CS (MNP–CS–TEL) showed pH-responsive controlled release characteristics. The MNP–CS–TEL showed dose dependent cytotoxicity towards PC-3 human prostate cancer cells. The results demonstrated the significant antitumor activity of designed nanoformulation.

Telmisartan, an Antagonist of Angiotensin II Receptors, Accentuates Voltage-Gated Na+ Currents and Hippocampal Neuronal Excitability.

Telmisartan (TEL), a non-peptide blocker of the angiotensin II type 1 receptor, is a widely used antihypertensive agent. Nevertheless, its neuronal ionic effects and how they potentially affect neuronal network excitability remain largely unclear. With the aid of patch-clamp technology, the effects of TEL on membrane ion currents present in hippocampal neurons (mHippoE-14 cells) were investigated. For additional characterization of the effects of TEL on hippocampal neuronal excitability, we undertook in vivo studies on Sprague Dawley (SD) rats using pilocarpine-induced seizure modeling, a hippocampal histopathological analysis, and inhibitory avoidance testing. In these hippocampal neurons, TEL increased the peak amplitude of INa, with a concomitant decline in the current inactivation rate. The TEL concentration dependently enhanced the peak amplitude of depolarization-elicited INa and lessened the inactivation rate of INa. By comparison, TEL was more efficacious in stimulating the peak INa and in prolonging the inactivation time course of this current than tefluthrin or (-)-epicatechin-3-gallate. In the continued presence of pioglitazone, the TEL-perturbed stimulation of INa remained effective. In addition, cell exposure to TEL shifted the steady-state inactivation INa curve to fewer negative potentials with no perturbations of the slope factor. Unlike chlorotoxin, either ranolazine, eugenol, or KMUP-1 reversed TEL-mediated increases in the strength of non-inactivating INa. In the cell-attached voltage-clamp recordings, TEL shortened the latency in the generation of action currents. Meanwhile, TEL increased the peak INa, with a concurrent decrease in current inactivation in HEKT293T cells expressing SCN5A. Furthermore, although TEL did not aggravate pilocarpine-induced chronic seizures and tended to preserve cognitive performance, it significantly accentuated hippocampal mossy fiber sprouting. Collectively, TEL stimulation of peak INa in combination with an apparent retardation in current inactivation could be an important mechanism through which hippocampal neuronal excitability is increased, and hippocampal network excitability is accentuated following status epilepticus, suggesting further attention to this finding.

Development of L-Lysine Amino Acid-Based Co-Crystal of Telmisartan Using Crystal Engineering Approach to Improve Solubility, Dissolution, and Micrometric Properties.

To develop a co-crytsal of Telmisartan for enhancing its solubility in water. Intermolecular interaction happens in crystal packing; it utilizes and helps to understand the design of new solid with their respective chemical and physical properties called crystal engineering. It is a blueprint of molecular solids with specific chemical and physical properties through an understanding and handling of intermolecular interaction for increasing the solubility, in case of poor water-soluble drugs. The study was taken under consideration with an aim to generate and synthesize a cocrystal form of Telmisartan (TEL) with L-lysine to improve its water solubility, dissolution, and micrometric properties. Using dry grinding technique, solvent evaporation and cooling crystallization, the results revealed a generation of co-crystals with enhanced solubility by liquid drop grinding method. Hence, this process was further explored to investigate various formulations and process parameters that could significantly affect the crystal solubility, dissolution, and micrometric properties. The solubility of TEL co-crystals was enhanced by L-lysine. Further, the optimized batch was subjected to its micrometric evaluation and physiochemical characterization like FT-IR, NMR, PXRD. The result of the micrometric evaluation showed better results as compared to standards. The dissolution studies also showed a better dissolution rate for TEL co-crystal tablets than TEL tablets formulation. Co-crystals of TEL with L-lysine showed better solubility and dissolution rate.

Telmisartan Exacerbates Cisplatin-Induced Nephrotoxicity in a Mouse Model.

Cisplatin (CDDP; cis-diamine dichloroplatinum)-induced nephrotoxicity is the main reason for dose limitations, which can reduce the efficacy of cancer treatment. Lower blood pressure and administration of renin angiotensin system (RAS) inhibitors have been reported as factors that exacerbate CDDP-induced nephrotoxicity; however, the detailed mechanisms remain unknown and the results of previous studies are conflicting. In this study, we examined the influence of various hypotensive drugs, including RAS inhibitors and calcium channel blockers, on CDDP-induced nephrotoxicity in BALB/c mice. The mice were divided into nine groups: (1) CDDP group (15 mg/kg CDDP), (2) AML group (5 mg/kg amlodipine), (3) ENA group (2.5 mg/kg enalapril), (4) telmisartan (TEL) group (10 mg/kg telmisartan), (5) LOS group (10 mg/kg losartan), (6) CDDP + AML group, (7) CDDP + ENA group, (8) CDDP + TEL group, and (9) CDDP + LOS group. Nephrotoxicity was evaluated by measuring serum creatinine (CRE) and blood urea nitrogen (BUN) levels. In addition, the kidney sections were stained with Masson's trichrome and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) to assess the renal fibrosis area and apoptotic area. Serum CRE and BUN levels were increased in the CDDP + ENA, CDDP + LOS, and CDDP + TEL groups compared to those in the CDDP alone group, and the CDDP + AML group showed an increasing trend. However, there was no correlation between ∆CRE or ∆BUN levels and ∆ systolic blood pressure. The CDDP + TEL group showed a significant increase in the renal fibrosis area. These results suggest that exacerbation of CDDP-induced nephrotoxicity is not correlated with systolic blood pressure but is associated with administration of RAS inhibitors, particularly TEL.

Design of telmisartan-weak acid solid dispersion to improve its solubility and stability

Telmisartan (TEL), an angiotensin II receptor antagonist, is widely used for the treatment of hypertension. However, low solubility of TEL has resulted in solubilized commercial products with alkalizers. On the contrary, our study aims to improve the solubility and dissolution rate by preparing a new TEL-solid dispersion (SD) using a weak acid. The SD formulations (SD1-0, TEL-tartaric acid-Aerosil®300 in a 1:5:3 wt ratio; SD1-6, TEL-tartaric acid-Aerosil®300: IR® in a 1:5:3:1 wt ratio) showed improved dissolution (%) by 1.19-/1.08-/1.16-fold and 1.15-/1.06-/1.11-fold compared to that of Micardis® in pH 1.2/distilled water/pH 6.8, respectively. The physical properties of the SD formulations were changed, including melting points, crystallization, and chemical interaction. Moreover, these SD formulations well maintained their stability for 12 months. In conclusion, the improved solubility and dissolution (%) of TEL in the SD formulations may result in improved bioavailability and efficacy as an anti-hypertensive substance in animals.

Microfluidics nanoprecipitation of telmisartan nanoparticles: effect of process and formulation parameters

A continuous microfluidic nanoprecipitation process has been investigated to prepare nanosized particles of a poorly water-soluble drug telmisartan (TEL), thereby enhancing its solubility and bioavailability. The present work aims to overcome agglomeration of drug particles by controlling the surface forces between the particles using various polymers like Polyvinylpyrrolidone K-30 (PVP K-30), Polyvinylpyrrolidone K-90 (PVP K-90), Poloxamer 188, Poloxamer 407, and hydroxypropyl methylcellulose (HPMC). The effect of process parameters such as solvent-to-antisolvent ratio, polymer-to-drug ratio, microchannel length, and solvent flow rate on drug particle size and polydispersity index (PDI) has been studied. The drug–polymer interaction investigated through X-ray diffraction (XRD) and Fourier transform infrared (FTIR) analysis revealed a significant reduction in peak intensity for Poloxamer 407 with no drug–polymer interaction. Also, the surface morphology of recrystallised TEL nanoparticles examined using field emission scanning electron microscopy (FESEM) showed clear and nearly uniform shaped particles. Poloxamer 407-based formulation of TEL exhibited minimum drug agglomeration with least particle size 369 nm and PDI value 0.049. The minimum particle size was achieved at solvent-to-antisolvent ratio 1:2, 1:1 polymer-to-drug ratio, microchannel length of 60 cm, and solvent flow rate of 30 mL/h. Thus, the microfluidic technique resulted in the production of TEL nanoparticles with narrow size distribution and useful morphological characteristics.

Efficiency evaluation of the photocatalytic degradation of telmisartan anti-hypertensive drug with Fenton, photo-Fenton and recyclable TiO2 heterogeneous catalyst

The photocatalytic degradation of telmisartan (TN), an anti-hypertensive drug was studied in aqueous media using different catalysts (Fenton, photo-Fenton and Titania (TiO2)) and different atmospheric conditions (air, oxygen (O2), air/hydrogen peroxide (air/H2O2), Oxygen/hydrogen peroxide O2/H2O2). In addition, the degradation experiments were also carried out using telmisartan based commercial tablets. The concentration of telmisartan during the degradation process was monitored by UV–Vis spectrophotometer. It has been found that O2/H2O2 atmospheric condition and into the presence of TiO2 shows higher degradation rate. The degradation was followed by pseudo-first order kinetics. The effect of various operating parameters such as concentration of telmisartan, dosage of the catalyst, pH and nature of irradiation was systematically studied. The mineralization trend of telmisartan was followed by TOC (total organic carbon) content and it was observed that complete mineralization could be achieved within a period of 3 h. The telmisartan metabolites or by-products during the degradation were analyzed and identified by GC–MS technique.

Chemo-Photothermal Combination Cancer Therapy with ROS Scavenging, Extracellular Matrix Depletion, and Tumor Immune Activation by Telmisartan and Diselenide-Paclitaxel Prodrug Loaded Nanoparticles.

Extracellular matrix (ECM) accumulating in the tumor microenvironment (TME) is generated by tumor-associated fibroblasts. It can elevate interstitial fluid pressure and form dense barriers in tumor tissues. Consequently, nanocarriers are hindered from permeating into deeper tumor sites. Thus, the programmed drug-releasing nanoparticles, G(TM)PPSP, were developed for TME remodeling and breast cancer therapy. Gelatin nanoparticles were linked with platinum nanoparticles (PtNPs) to obtain G(TM)PPSP with a size of 214.0 ± 5.0 nm. Telmisartan (TM) was loaded in gelatin nanoparticles. Paclitaxel (PTX) was attached to PtNPs via a dual redox responsive diselenide bond. TM release was mediated by MMP-2 because of gelatin degradation in TME, and then intracellular PTX was released because of diselenide linkage fracture triggered by ROS or glutathione. ECM was depleted owing to TGF-β downregulation by TM and direct ablation by the photothermal effect of PtNPs. 4T1 tumor progression was inhibited by PTX chemotherapy, intracellular ROS scavenging of PtNPs, and photothermal therapy (PTT). The tumor spheroid penetration assay proved G(TM)PPSP could permeate into deep tumor regions when MMP-2 existed. In vivo antitumor experiments implied G(TM)PPSP with PTT could inhibit tumor growth effectively and remodel TME via ECM depletion and immunity activation, indicating the potential of G(TM)PPSP-based chemo-photothermal combination therapy for breast cancer treatment.

A Design of Experiment (DoE) based approach for development and optimization of nanosuspensions of telmisartan, a BCS class II antihypertensive drug

BackgroundThe present study was aimed to enhance the solubility and dissolution of BCS class II drug, telmisartan (TEM), by nanoformulation approach. Several attempts were made to develop a nanosuspension by bottom-up and top-down techniques. In our study, we found in situ nanoamorphization technique to be incompatible and hence was not selected for further development of nanoformulation. Bottom-up techniques such as anti-solvent precipitation and emulsification solvent evaporation methods failed to reduce the size of the drug to nanoform by HPMC E15 and PVP K-25 at 1500–2000 rpm but resulted in micron-sized particles.ResultsHowever, the acid-base neutralization method has produced nanosuspension with a particle size of 243.9 nm and 0.119 PDI. Formulation and analytical development were carried out by statistical factorial design using the Design-Expert software (version 11.0). The nanosuspensions remained stable even after 90 days without any aggregations with particle size 338.1 nm and PDI 0.146. Zeta potential of optimized formulation was found to be − 16.2 mV. Drug content and its release were estimated by the developed and validated in-house HPLC method. In vitro drug diffusion studies on the optimized formulation have shown a drug release of 82.6% by the end of 3 h, whereas plain drug suspension has shown only 42.8% release, indicating a 2-fold increase of drug diffusion with nanosuspension. Ex vivo drug permeation studies performed using excised goat gastric mucosa revealed much faster permeation of TEM from nanosuspension than the plain drug suspension.ConclusionsHence, from the results, it can be concluded that TEM, when formulated by acid-base neutralization method as a nanosuspension, leads to enhanced solubility, dissolution, and stability.

Analytical Methods for the Determination of Sartans in Pharmaceutical Formulations and Biological Fluids: A Review

Background:Sartans are mostly used as a part of combination with additional medicines in the therapy of essencial hypertension. Preferred combinations are ARB and thiazide diuretics (Hydrochlorothiazide (HCT) and Chlorthalidone (CHL)) or ARB and calcium antagonists. The number of sartans mostly prescribed by specialists is only seven - Candesartan (CDS), Eprosartan (EPS), Irbesartan (IBS), Losartan (LOS), Olmesartan (OMS), Telmisartan (TMS) and Valsartan (VLS).Methods:The widespread use of sartans in the treatment of hypertension requires reliable methods of analysis. Bulk drugs and pharmaceutical preparations should be analyzed to ensure the quality of the medicinal products reaching patients. On the other hand, the analysis of drugs in biological fluids aims to trace and improve patient care by adjusting the therapeutic doses of drugs. According to our knowledge, a review devoted to the analysis of sartans was published in 2014.Results:Spectral methods are widely used in the analysis of bulk drugs and pharmaceutical dosage forms due to their relatively simple procedures, low reagent and sample consumption, speed, precision and accuracy combined with accessibility and comparatively low cost of common apparatus. Many papers for determination of sartans in bulk drugs and pharmaceutical preparations based on liquid chromatographic techniques were published in the available literature. Among these methods, HPLC takes the leading place but UPLC and HPTLC are also present.Conclusion:The widespread use of sartans in the treatment of hypertension requires reliable methods of analysis. Bulk drugs and pharmaceutical preparations should be analyzed to ensure the quality of the medicinal products reaching patients. On the other hand, the analysis of drugs in biological fluids aims to trace and improve patient care by adjusting the therapeutic doses of drugs. Since 2014, many articles have been published on the sartans analysis and this provoked our interest to summarize the latest applications in the analysis of sartans in pharmaceutical formulations and biological media. Articles published from 2014 to 2018 are covered.

Spectroscopic and molecular docking studies for characterizing binding mechanism and conformational changes of human serum albumin upon interaction with Telmisartan

Human serum albumin (HSA), one of the most copious plasma proteins is responsible for binding and transportation of many exogenous and endogenous ligands including drugs. In this study, we intended to explore the extent and types of binding interaction present between HSA and the antihypertensive drug, telmisartan (TLM). The conformational changes in HSA due to this binding were also studied using different spectroscopic and molecular docking techniques. The spectral shifting and intensity variations upon interaction with TLM were studied using FT-IR spectroscopy. Binding constant and the change in absorption of HSA at its λmax was analyzed using absorption spectroscopy. Eventually, the types and extent of binding interactions were confirmed using molecular docking technique. Results have shown that TLM significantly interacts with the binding site-1 of HSA utilizing strong hydrogen bonding with Glu292, and Lys195 residues. The UV-absorption intensities were found to be decreased serially as the drug concentration increased with a binding constant of 1.01 × 103 M−1. The secondary structure analysis using FT-IR spectroscopy also revealed a marked reduction in the α-helix (56%) component of HSA on interaction. This study gives critical insights into the interaction of TLM with HSA protein which eventually affects the concentration of TLM reaching the site of action and ultimately its therapeutic profile.

Co-Amorphous Telmisartan-Pimelic Acid with Improved Solubility

Telmisartan (TEL), a type of antihypertensive drug, has poor solubility. To improve its solubility, the co-amorphous telmisartan with pimelic acid (PA) in molar ratio of 1:1 and 2:1, respectively, were obtained using a liquid-assisted grinding method. The co-amorphous system was characterized by the powder X-ray diffraction and differential scanning calorimetry. The molecular interactions of the co-amorphous were studied by the infrared spectra. After the formation of co-amorphous, the solubility of TELwas much improved, and the apparent solubility values were approximately 9-15 times as high as that of crystalline TEL. Moreover, the co-amorphous TEL-PA was stored under 25 °C/20% RH for a month without any evidence of conversion by powder X-ray diffraction analysis.

Smart analysis of a ternary mixture of amlodipine, hydrochlorothiazide and telmisartan by manipulation of UV spectra: Development, validation and application to formulations

Three simple UV spectrophotometric methods were established and validated for the concurrent estimation of a ternary mixture of an antihypertensive formulation consisting of amlodipine (AMD), hydrochlorothiazide (HCZ) and telmisartan (TEL) using 50% v/v ethanol-water as solvent. The first method was based on the determination of AMD using zero-order spectra (371.0 nm), whereas, HCZ and TEL were quantified by measuring the peak height at zero crossing wavelength of the second derivative of ratio spectra (279.4 nm and 314.7 nm). The second procedure was accomplished by determining the absorption difference between peak and trough at two different wavelengths of double devisor ratio spectra (369.4 nm–297.5 nm for AMD; 272.1 nm–241.5 nm for HCZ; 297.2 nm–272.7 nm for TEL) The third method involved the measurement of the peak amplitude of maxima or minima of first derivative spectra of double devisor ratio spectra. (390.4 nm for AMD, 278.9 nm for HCZ 288.1 nm for TEL) All the drugs showed good linearity with an acceptable correlation coefficient in all the three proposed methods. Further accuracy, precision, sensitivity, robustness, recovery studies and selectivity were determined according to the ICH strategies and the results were in agreement with the acceptable range. In addition, the proposed techniques were applied effectively for quantification of AMD, HCZ and TEL from the solid dosage form. The comparison of assay outcomes, using the student’s t-test and F test, revealed that there is no significant change among the proposed UV and the reported HPLC procedures. The manipulation of UV spectra is simple, fast, and the proposed methods were environment friendly and economical when compared to very expensive chromatographic methods. Hence, these procedures can be employed for the routine quality control examination in industries and laboratories.

NOVEL PHARMACEUTICAL COCRYSTAL OF TELMISARTAN AND HYDROCHLOROTHIAZIDE

Objective: Telmisartan (TEL), commonly used antihypertensive, is poorly soluble in water and has limited and variable bioavailability. Commercially, TEL is available as a single drug and in combination with hydrochlorothiazide (HYZ). Researchers have developed cocrystals of TEL with coformers, namely, oxalic acid, glutaric acid, and saccharin. An attempt was made to prepare the cocrystals of TEL with HYZ, an active pharmaceutical ingredient (API) itself so that both the APIs are available in a single tablet. The present study was aimed at enhancement in solubility of TEL by formation of its cocrystals.
 Methods: The cocrystals of TEL with HYZ, in different stoichiometric ratios (1:0.5, 1:1, and 1:2), were prepared by solvent coevaporation and liquid-assisted grinding methods. The cocrystals, consisting of TEL:HYZ (in 1:0.5 ratio and 1:1 ratio), depicted maximum yield, drug content, saturation solubility, and flow properties. These cocrystals were characterized by X-ray analysis, infrared spectroscopy, and thermal analysis.
 Results: The crystal structure of TEL-HYX revealed that it was a cocrystal, since no proton was transferred between the TEL and HYZ molecules. It was predicted that two molecules are associated through a hydrogen bond between an acidic group of TEL and sulfonamido group of HYZ. The cocrystallization improved the solubility of TEL 7 times. In vitro release rate of tablets of cocrystals was higher than that of marketed TEL tablets. HYZ has a potential to form the cocrystals of TEL.
 Conclusion: The objective of improvement in the solubility of TEL was successfully achieved by the formation of cocrystals of TEL: HYZ.

Telmisartan prevents development of obesity and normalizes hypothalamic lipid droplets.

The AT1 receptor blocker telmisartan (TEL) prevents diet-induced obesity. Hypothalamic lipid metabolism is functionally important for energy homeostasis, as a surplus of lipids induces an inflammatory response in the hypothalamus, thus promoting the development of central leptin resistance. However, it is unclear as to whether TEL treatment affects the lipid status in the hypothalamus. C57BL/6N mice were fed with chow (CONchow) or high-fat diet (CONHFD). HFD-fed mice were gavaged with TEL (8 mg/kg/day, 12 weeks, TELHFD). Mice were phenotyped regarding weight gain, energy homeostasis, and glucose control. Hypothalamic lipid droplets were analyzed by fluorescence microscopy. Lipidomics were assessed by performing liquid chromatography-mass spectrometry in plasma and hypothalami. Adipokines were investigated using immunosorbent assays. Glial fibrillary acidic protein (GFAP) was determined by Western blotting and immunohistochemical imaging. We found that body weight, energy homeostasis, and glucose control of TEL-treated mice remained normal while CONHFD became obese. Hypothalamic ceramide and triglyceride levels as well as alkyne oleate distribution were normalized in TELHFD. The lipid droplet signal in the tanycyte layer was higher in CONHFD than in CONchow and returned to normal under TELHFD conditions. High hypothalamic levels of GFAP protein indicate astrogliosis of CONHFD mice while normalized GFAP, TNFα, and IL1α levels of TELHFD mice suggest that TEL prevents hypothalamic inflammation. In conclusion, TEL has anti-obese efficacy and prevented lipid accumulation and lipotoxicity, which is accompanied by an anti-inflammatory effect in the murine hypothalamus. Our findings support the notion that a brain-related mechanism is involved in TEL-induced weight loss.