A Novel Co-Crystal of Bexarotene and Ligustrazine Improves Pharmacokinetics and Tissue Distribution of Bexarotene in SD Rats

Ren, Shuyue; Jiao, Lingtai; Yang, Shumei; Zhang, Li; Song, Junke; Yu, Haoying; Wang, Jingrong; Lv, Tingting; Sun, Lan; Lü, Yang; Du, Guanhua

doi:10.3390/pharmaceutics12100906

Cited by 16 publications

(19 citation statements)

References 61 publications

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“…To investigate whether the plasma concentration of cocrystal in rats increased compared with API, we performed a pharmacokinetics experiment of cocrystal PRA-FA in vivo [ 26 , 27 ]. SD rats were randomly divided into three groups with two rats in each group.…”

Section: Methodsmentioning

confidence: 99%

Cocrystals of Praziquantel with Phenolic Acids: Discovery, Characterization, and Evaluation

Yang

Liu

et al. 2022

Molecules

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Solvent-assisted grinding (SAG) and solution slow evaporation (SSE) methods are generally used for the preparation of cocrystals. However, even by using the same solvent, active pharmaceutical ingredient (API), and cocrystal coformer (CCF), the cocrystals prepared using the two methods above are sometimes inconsistent. In the present study, in the cocrystal synthesis of praziquantel (PRA) with polyhydroxy phenolic acid, including protocatechuic acid (PA), gallic acid (GA), and ferulic acid (FA), five different cocrystals were prepared using SAG and SSE. Three of the cocrystals prepared using the SAG method have the structural characteristics of carboxylic acid dimer, and two cocrystals prepared using the SSE method formed cocrystal solvates with the structural characteristics of carboxylic acid monomer. For phenolic acids containing only one phenolic hydroxyl group (ferulic acid), when preparing cocrystals with PRA by using SAG and SSE, the same product was obtained. In addition, the weak molecular interactions that were observed in the cocrystal are explained at the molecular level by using theoretical calculation methods. Finally, the in vitro solubility of cocrystals without crystal solvents and in vivo bioavailability of PRA-FA were evaluated to further understand the influence on the physicochemical properties of API for the introduction of CCF.

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Section: Methodsmentioning

confidence: 99%

Cocrystals of Praziquantel with Phenolic Acids: Discovery, Characterization, and Evaluation

Yang

Liu

et al. 2022

Molecules

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“… a In vitro activity data as well as physicochemical and PK parameters for 2 were derived from the literature. ,, PK parameters refer to p.o. administration.…”

Section: Discussionmentioning

confidence: 99%

“…The nuclear retinoid X receptor (RXR) comprises a ligand-activated transcription factor family existing in three highly conserved isoforms (RXRα, NR2B1; RXRβ, NR2B2; and RXRγ, NR2B3). , The RXRs fulfill a central role in the nuclear receptor superfamily acting not only as universal heterodimer partners but also as homodimers regulating gene expression. Several fatty acids and vitamin A metabolites have been discovered as RXR agonists among which 9- cis retinoic acid ( 1 , Chart ) is the most potent ligand. − As the only approved synthetic rexinoid, bexarotene ( 2 ) is used as second-line treatment in cancer; ,, however, its use has been associated with severe adverse effects. , Considerable preclinical evidence suggests a high therapeutic potential of RXR activation to counteract neurodegenerative diseases such as multiple sclerosis − and Alzheimer’s disease. − Despite recent progress in targeting RXRs, ,− new potent RXR agonists are needed to overcome the limitations of traditional rexinoids, such as exceptional lipophilicity, poor pharmacokinetics (PK), and pronounced toxicity, ,− to further probe and exploit the highly promising pharmacological potential of RXR modulation.…”

Section: Introductionmentioning

confidence: 99%

“…Some compounds were purified by preparative HPLC using a Shimadzu preparative LC-20A Prominence (Shimadzu, Kyoto, Japan) with the following conditions: column, Luna (10μ C18(2) 100 Å; 250 × 21.2 mm; Phenomenex, Torrance, CA, U.S.A.); mobile phase, linear gradient from 50% ACN to 90% within 10 min, 90% ACN for 5 min, linear gradient from 90% ACN to 50% within 1 min, 50% 37 as well as physicochemical 20 and PK parameters for 2 were derived from the literature. 22,25,38 28 3-(4-Phenyloxazol-2-yl)propanoic Acid (10). 4-Oxo-4-(2-oxo-2phenylethoxy)butanoic acid (133, 1.24 g, 5.23 mmol, 1.00 equiv), acetamide (1.56 g, 26.1 mmol, 5.00 equiv), and BF 3 •Et 2 O (0.740 g, 5.23 mmol, 1.00 equiv) were mixed and stirred at 140 °C for 16 h. After cooling to rt, aqueous hydrochloric acid (10%, 30 mL) was added and the mixture was extracted with EtOAc (3 × 30 mL).…”

Section: ■ Introductionmentioning

confidence: 99%

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Oxaprozin Analogues as Selective RXR Agonists with Superior Properties and Pharmacokinetics

et al. 2021

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The retinoid X receptors (RXR) are ligand-activated transcription factors involved in multiple regulatory networks as universal heterodimer partners for nuclear receptors. Despite their high therapeutic potential in many pathologies, targeting of RXR has only been exploited in cancer treatment as the currently available RXR agonists suffer from exceptional lipophilicity, poor pharmacokinetics (PK), and adverse effects. Aiming to overcome the limitations and to provide improved RXR ligands, we developed a new potent RXR ligand chemotype based on the nonsteroidal anti-inflammatory drug oxaprozin. Systematic structure–activity relationship analysis enabled structural optimization toward low nanomolar potency similar to the well-established rexinoids. Cocrystal structures of the most active derivatives demonstrated orthosteric binding, and in vivo profiling revealed superior PK properties compared to current RXR agonists. The optimized compounds were highly selective for RXR activation and induced RXR-regulated gene expression in native cellular and in vivo settings suggesting them as excellent chemical tools to further explore the therapeutic potential of RXR.

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“…A 15-μL sample was injected by autosampler and monitored at a wavelength of 260 nm. The calibration curve was linear and had a correlation coefficient (R 2 > 0.9996) for 0.25-16 μg/ml concentration range [27,28].…”

Section: High-performance Liquid Chromatography Methodsmentioning

confidence: 99%

Determination of Alteration in Micromeritic Properties of a Solid Dispersion: Brunauer-Emmett-Teller Based Adsorption and Other Structured Approaches

et al. 2022

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The present study is focused on the use of solid dispersion technology to triumph over the solubility-related problems of bexarotene which is currently used for treating various types of cancer and has shown potential inhibitory action on COVID-19 main protease and human ACE2 receptors. It is based on comparison of green locust bean gum and synthetic poloxamer as polymers using extensive mechanistic methods to explore the mechanism behind solubility enhancement and to find suitable concentration of drug to polymer ratio to prepare porous 3 rd generation solid dispersion. The prepared solid dispersions were characterized using different studies like X-ray diffraction (XRD), thermal gravimetric analysis (TGA), scanning electron microscopy (SEM), Brunauer-Emmett-Teller (BET), differential scanning calorimetry (DSC), and particle size analysis in order to determine the exact changes occurred in the product which are responsible for enhancing solubility profiles of an insoluble drug. The results showed different profiles for particle size, solubility, dissolution rate, porosity, BET, and Langmuir specific surface area of prepared solid dispersions by using different polymers. In addition to the comparison of polymers, the BET analysis deeply explored the changes occurred in all dispersions when the concentration of polymer was increased. The optimized solid dispersion prepared with MLBG using lyophilization technique showed reduced particle size of 745.7±4.4 nm, utmost solubility of 63.97%, pore size of 211.597 Å, BET and Langmuir specific surface area of 5.6413 m 2 /g and 8.2757 m 2 /g, respectively.

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A Novel Co-Crystal of Bexarotene and Ligustrazine Improves Pharmacokinetics and Tissue Distribution of Bexarotene in SD Rats

Cited by 16 publications

References 61 publications

Cocrystals of Praziquantel with Phenolic Acids: Discovery, Characterization, and Evaluation

Cocrystals of Praziquantel with Phenolic Acids: Discovery, Characterization, and Evaluation

Oxaprozin Analogues as Selective RXR Agonists with Superior Properties and Pharmacokinetics

Determination of Alteration in Micromeritic Properties of a Solid Dispersion: Brunauer-Emmett-Teller Based Adsorption and Other Structured Approaches

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