Improved in vitro and in vivo properties of telmisartan in the co-amorphous system with hydrochlorothiazide: A potential drug-drug interaction mechanism prediction

Shi, Xiangjun; Zhou, Xiyue; Shen, Shuimei; Chen, Qifeng; Song, Shengjie; Gu, Chenru; Wang, Chao

doi:10.1016/j.ejps.2021.105773

Cited by 21 publications

(9 citation statements)

References 37 publications

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“…The physical stability test suggested a coamorphous formation at a molar ratio of 1:1 between TMS and AML. Previously, a coamorphous formulation of TMS and hydrochlorothiazide via hydrogen bonding showed a crystalline peak of TMS after storage for 90 days at 40 °C and 75% RH . Furthermore, the coamorphous TMS-arginine formulation was not stable for three months under the same conditions .…”

Section: Resultsmentioning

confidence: 97%

“…Previously, a coamorphous formulation of TMS and hydrochlorothiazide via hydrogen bonding showed a crystalline peak of TMS after storage for 90 days at 40 °C and 75% RH. 32 Furthermore, the coamorphous TMS-arginine formulation was not stable for three months under the same conditions. 33 Given the stability of these formulations, the excellent physical stability of the TMS/AML (1:1) formulation may be related to intermolecular interactions between TMS and AML.…”

Section: ■ Results and Discussionmentioning

confidence: 97%

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Designing a Novel Coamorphous Salt Formulation of Telmisartan with Amlodipine to Enhance Permeability and Oral Absorption

et al. 2023

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Coamorphous formulation is a useful approach for enhancing the solubility of poorly water-soluble drugs via intermolecular interactions. In this study, a hydrogen-bondingbased coamorphous system was developed to improve drug solubility, but it barely changed the apparent permeability (P app ) of the drug. This study aimed to design a novel coamorphous salt using ionic interactions to improve drug permeability and absorption. Telmisartan (TMS), with an acidic group, was used to form a coamorphous salt with basic amlodipine (AML). Evaluation of the physicochemical properties confirmed the formation of a coamorphous salt via ionic interactions between the amine group of AML and the carboxyl group of TMS at a molar ratio of 1:1. The coamorphous salt of TMS/AML enhanced the partitioning of both drugs into octanol, indicating increased lipophilicity owing to the interaction between TMS and AML. The coamorphous salt dramatically enhanced TMS solubility (99.8 times that of untreated TMS) and decreased AML solubility owing to the interaction between TMS and AML. Although the coamorphous salt showed a decreased P app in the permeation study in the presence of a thicker unstirred water layer (UWL) without stirring, P app increased in the presence of a thinner UWL with stirring. The oral absorption of TMS from the coamorphous salt increased by up to 4.1 times compared to that of untreated TMS, whereas that of AML remained unchanged. Although the coamorphous salt with increased lipophilicity has a disadvantage in terms of diffusion through the UWL, the UWL is thin in human/animal bodies owing to the peristaltic action of the digestive tract. Dissociation of the coamorphous salt on the membrane surface could contribute to the partitioning of the neutral form of drugs to the membrane cells compared with untreated drugs. As a result, coamorphous salt formation has the advantage of improving the membrane permeation and oral absorption of TMS, owing to the enhanced solubility and supply of membrane-permeable free TMS on the surface of the membrane.

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Section: Resultsmentioning

confidence: 97%

Section: ■ Results and Discussionmentioning

confidence: 97%

Designing a Novel Coamorphous Salt Formulation of Telmisartan with Amlodipine to Enhance Permeability and Oral Absorption

et al. 2023

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“…LEN belongs to the biopharmaceutics classification system (BCS) II or IV drugs with poor water solubility [37]; similarly, TEL is a poorly water-soluble drug that belongs to BCS II, and solubility is related to PH [38]. Therefore, the PH of the mobile phase affects the separation of TEL.…”

Section: Uplc-ms/ms Methods Developmentmentioning

confidence: 99%

A Simple UPLC/MS-MS Method for Simultaneous Determination of Lenvatinib and Telmisartan in Rat Plasma, and Its Application to Pharmacokinetic Drug-Drug Interaction Study

Cui¹,

Xiao

et al. 2022

Molecules

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Lenvatinib is a multi-targeted tyrosine kinase inhibitor that inhibits tumor angiogenesis, but hypertension is the most common adverse reaction. Telmisartan is an angiotensin receptor blocker used to treat hypertension. In this study, a simple ultra-performance liquid chromatography-tandem mass spectrometry method was developed for the simultaneous determination of lenvatinib and telmisartan, and it was applied to the pharmacokinetic drug interaction study. Plasma samples were treated with acetonitrile to precipitate protein. Water (containing 5 mM of ammonium acetate and 0.1% formic acid) and acetonitrile (0.1% formic acid) were used as the mobile phases to separate the analytes with gradient elution using a column XSelect HSS T3 (2.1 mm × 100 mm, 2.5 μm). Multiple reaction monitoring in the positive ion mode was used for quantification. The method was validated and the precision, accuracy, matrix effect, recovery, and stability of this method were reasonable. The determination of analytes was not interfered with by other substances in the blank plasma, and the calibration curves of lenvatinib and telmisartan were linear within the range of 0.2–1000 ng/mL and 0.1–500 ng/mL, respectively. The results indicate that lenvatinib decreased the systemic exposure of telmisartan. Potential drug interactions were observed between lenvatinib and telmisartan.

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“…The drug–drug co-amorphous systems provide an alternative strategy for drug combination while improving physicochemical properties. The drug–drug co-amorphous forms of telmisartan-hydrochlorothiazide, felodipine-indomethacin, indomethacin-paracetamol, ursolic acid-piperine, and others − have already been reported.…”

Section: Introductionmentioning

confidence: 96%

Co-amorphous Systems of Sinomenine with Platensimycin or Sulfasalazine: Physical Stability and Excipient-Adjusted Release Behavior

Chen

Zhang

et al. 2022

Mol. Pharmaceutics

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There is strong interest to develop affordable treatments for the infection-associated rheumatoid arthritis (RA). Here, we present a drug−drug co-amorphous strategy against RA and the associated bacterial infection by the preparation and characterization of two co-amorphous systems of sinomenine (SIN) with platensimycin (PTM) or sulfasalazine (SULF), two potent antibiotics. Both of them were comprehensively characterized using powder Xray diffraction, temperature-modulated differential scanning calorimetry, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The co-amorphous forms of SIN-PTM and SIN-SULF exhibited high T g s at 139.10 ± 1.0 and 153.3 ± 0.2 °C, respectively. After 6 months of accelerated tests and 1 month of drug-excipient compatibility experiments, two coamorphous systems displayed satisfactory physical stability. The formation of salt and strong intermolecular interactions between SIN and PTM or SULF, as well as the decreased molecular mobility in co-amorphous systems, may be the intrinsic mechanisms underlying the excellent physical stability of both co-amorphous systems. In dissolution tests, two co-amorphous systems displayed distinct reduced SINaccumulative releases (below 20% after 6 h of release experiments), which may lead to its poor therapeutic effect. Hence, we demonstrated a controlled release strategy for SIN by the addition of a small percentage of polymers and a small-molecule surfactant to these two co-amorphous samples as convenient drug excipients, which may also be used to improve the unsatisfactory dissolution behaviors of the previously reported SIN co-amorphous systems. Several hydrogen bonding interactions between SIN and PTM or SULF could be identified in NMR experiments in DMSO-d 6 , which may be underlying reasons of decreased dissolution behaviors of both co-amorphous forms. These drug−drug co-amorphous systems could be a potential strategy for the treatment of infectionassociated RA.

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Improved in vitro and in vivo properties of telmisartan in the co-amorphous system with hydrochlorothiazide: A potential drug-drug interaction mechanism prediction

Cited by 21 publications

References 37 publications

Designing a Novel Coamorphous Salt Formulation of Telmisartan with Amlodipine to Enhance Permeability and Oral Absorption

Designing a Novel Coamorphous Salt Formulation of Telmisartan with Amlodipine to Enhance Permeability and Oral Absorption

A Simple UPLC/MS-MS Method for Simultaneous Determination of Lenvatinib and Telmisartan in Rat Plasma, and Its Application to Pharmacokinetic Drug-Drug Interaction Study

Co-amorphous Systems of Sinomenine with Platensimycin or Sulfasalazine: Physical Stability and Excipient-Adjusted Release Behavior

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