Statistical approach for solidifying ticagrelor loaded self-microemulsifying drug delivery system with enhanced dissolution and oral bioavailability

Na, Young-Guk; Byeon, Jin‐Ju; Wang, Miao; Huh, Hyun Wook; Kim, Min-Ki; Bang, Ki-Hyun; Han, Min-Gu; Lee, Hong-Ki; Cho, Cheong-Weon

doi:10.1016/j.msec.2019.109980

Cited by 20 publications

(14 citation statements)

References 36 publications

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“… 39 However, they sometimes entail incomplete desorption of micelle components because of strong interaction between the drug and silicates. 40 In comparison, cellulose-based diluents are hydrophilic and completely dissolve in aqueous phase, avoiding the problems of incomplete desorption. 28 In this regard, a combination of these solid carriers would be preferred.…”

Section: Resultsmentioning

confidence: 99%

“…47 Water-insoluble silicates exert disadvantage on the dissolution rate due to molecular adhesion (eg, hydrophobic interaction) between the silanol group and micelle components, which resulted in a negative association with both Y 1 and Y 2 . 40 In contrast, VP105 is completely soluble in water and enables complete desorption of the micelle components into the aqueous medium. 28 Nevertheless, X 3 was negatively associated with Y 1 because Y 1 reflected dissolution behavior in the early phase only.…”

Section: Resultsmentioning

confidence: 99%

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Development of a Solid Supersaturable Micelle of Revaprazan for Improved Dissolution and Oral Bioavailability Using Box-Behnken Design

Goo¹,

Sa²,

Choi³

et al. 2021

IJN

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Purpose To enhance the oral bioavailability of revaprazan (RVP), a novel solid, supersaturable micelle (SSuM) was developed. Methods Surfactants and solid carriers were screened based on a solubility and a flowability test, respectively. Supersaturating agents, including Poloxamer 407 (P407), were screened. The SSuM was optimized using a Box-Behnken design with three independent variables, including Gelucire 44/14:Brij L4 (G44/BL4; X 1 ) and the amounts of Florite PS-10 (FLO; X 2 ) and Vivapur 105 (VP105; X 3 ), and three response variables, ie, dissolution efficiency at 30 min (Y 1 ), dissolution enhancing capacity (Y 2 ), and Carr’s index (Y 3 ). The solid state property was evaluated, and a dissolution test was conducted. RVP, Revanex ® , solid micelle (P407-free from the composition of SSuM), and SSuM were orally administrated to rats (RVP 20 mg equivalent/kg) for in vivo pharmacokinetic study. Results G44 and BL4 showed great solubility, with a critical micelle concentration range of 119.2–333.0 μg/mL. P407 had an excellent supersaturating effect. FLO and VP105 were selected as solid carriers, with a critical solidifying ratio (g/mL) of 0.30 and 0.91, respectively. With optimized values of X 1 (–0.41), X 2 (0.31), and X 3 (–0.78), RVP (200 mg)-containing SSuM consisting of G44 (253.8 mg), BL4 (106.2 mg), FLO (99.3 mg), VP105 (199.8 mg), and P407 (40 mg) was developed, resulting in Y 1 (40.3%), Y 2 (0.008), and Y 3 (12.3%). RVP existed in an amorphous state in the optimized SSuM, and the SSuM formed a nanosized dispersion in the aqueous phase, with approximately 71.7% dissolution at 2 h. The optimized SSuM improved the relative bioavailability of RVP in rats by approximately 478%, 276%, and 161% compared to raw RVP, Revanex ® , and solid micelle, respectively. Conclusion The optimized SSuM has great potential for the development of solidified formulations of poorly water-soluble drugs with improved oral absorption.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Development of a Solid Supersaturable Micelle of Revaprazan for Improved Dissolution and Oral Bioavailability Using Box-Behnken Design

Goo¹,

Sa²,

Choi³

et al. 2021

IJN

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“…Statistical models for Y 1 , Y 2 , Y 3 , and Y 4 were proposed as linear, special quadratic, linear, and cubic models, respectively. Statistical parameters such as p -value, lack of fit, R 2 , adjusted R 2 , and predicted R 2 were investigated as indicators for determining the fit of statistical models [ 14 ]. The sequential p -value indicated that the suggested model was significant at a 95% confidence level, which was less than 0.05 in all models.…”

Section: Resultsmentioning

confidence: 99%

“…Self-microemulsifying drug delivery systems (SME) are often used to increase the dissolution of orally administered drugs [ 13 ]. SME formulation is an isotropic mixture of oil, surfactant, and cosurfactant that can be dispersed in GI fluids to form micro- or nano-emulsions with nanosized droplets [ 14 ]. The droplet size (100–300 nm) is much smaller than the particle size of raw materials (10–1000 µm), which can significantly improve dissolution and permeability [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Development and Evaluation of Docetaxel-Phospholipid Complex Loaded Self-Microemulsifying Drug Delivery System: Optimization and In Vitro/Ex Vivo Studies

et al. 2020

Self Cite

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Docetaxel (DTX) has clinical efficacy in the treatment of breast cancer, but it is difficult to develop a product for oral administration, due to low solubility and permeability. This study focused on preparing a self-microemulsifying drug delivery system (SME) loaded with DTX-phospholipid complex (DTX@PLC), to improve the dissolution and gastrointestinal (GI) permeability of DTX. A dual technique combining the phospholipid complexation and SME formulation described as improving upon the disadvantages of DTX has been proposed. We hypothesized that the complexation of DTX with phospholipids can improve the lipophilicity of DTX, thereby increasing the affinity of the drug to the cell lipid membrane, and simultaneously improving permeability through the GI barrier. Meanwhile, DTX@PLC-loaded SME (DTX@PLC-SME) increases the dissolution and surface area of DTX by forming a microemulsion in the intestinal fluid, providing sufficient opportunity for the drug to contact the GI membrane. First, we prepared DTX@PLC-SME by combining dual technologies, which are advantages for oral absorption. Next, we optimized DTX@PLC-SME with nanosized droplets (117.1 nm), low precipitation (8.9%), and high solubility (33.0 mg/g), which formed a homogeneous microemulsion in the aqueous phase. Dissolution and cellular uptake studies demonstrated that DTX@PLC-SME showed 5.6-fold higher dissolution and 2.3-fold higher DTX uptake in Caco-2 cells than raw material. In addition, an ex vivo gut sac study confirmed that DTX@PLC-SME improved GI permeability of DTX by 2.6-fold compared to raw material. These results suggested that DTX@PLC-SME can significantly overcome the disadvantages of anticancer agents, such as low solubility and permeability.

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“…The antiplatelet activity of ticagrelor is mainly dependent on the parent compound in addition to its metabolites. However, the average absolute oral bioavailability of ticagrelor is relatively low due to the first-pass effect of the intestine and liver and its rapid metabolism (Na et al, 2019). Noteworthy, it has been reported that ticagrelor is predominantly metabolized by CYP3A enzyme and the parent compound is the substrate of P-glycoprotein (P-gp; Teng, 2012).…”

Section: Introductionmentioning

confidence: 99%

Untargeted metabolomics reveals the mechanism of quercetin enhancing the bioavailability of ticagrelor

Zhang

Sun

Wei

et al. 2021

Biomedical Chromatography

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Ticagrelor is a first-line clinical drug for the treatment of acute coronary syndrome, but its oral bioavailability is relatively low. Flavonoids (polyphenol compounds commonly found in plant foods) seriously affect human metabolism and health. This study compared the effects of quercetin, luteolin and catechin on the pharmacokinetic parameters of ticagrelor and found that quercetin can significantly increase the C max and area under the curve from time zero to 36 h (AUC 0-36 ) of ticagrelor, that is, quercetin can enhance the bioavailability of ticagrelor, but luteolin and catechin cannot.The difference between the ticagrelor group and the combination of quercetin and ticagrelor was analyzed through untargeted metabolomics methods and multivariate data analysis, which identified changes in the levels of seven metabolites (deoxycholic acid, taurocholic acid, glycocholic acid, glycoursodeoxycholic acid, tryptophan, phenylalanine and kynurenine). Based on the changes of these metabolites, we found that the metabolic pathways of phenylalanine, tyrosine and tryptophan and the biosynthetic pathway of bile acids were changed. A metabolomics study revealed that quercetin improves the oral bioavailability of ticagrelor and that this might rely on changing the metabolic pathways of phenylalanine, tyrosine and tryptophan and the biosynthetic pathway of bile acids. The research results at the metabolic level provide us with a strong basis and direction for further exploring the mechanism underlying quercetin's ability to enhance the bioavailability of ticagrelor, and this may be useful for finding new agents that enhance the bioavailability.

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Statistical approach for solidifying ticagrelor loaded self-microemulsifying drug delivery system with enhanced dissolution and oral bioavailability

Cited by 20 publications

References 36 publications

Development of a Solid Supersaturable Micelle of Revaprazan for Improved Dissolution and Oral Bioavailability Using Box-Behnken Design

Development of a Solid Supersaturable Micelle of Revaprazan for Improved Dissolution and Oral Bioavailability Using Box-Behnken Design

Development and Evaluation of Docetaxel-Phospholipid Complex Loaded Self-Microemulsifying Drug Delivery System: Optimization and In Vitro/Ex Vivo Studies

Untargeted metabolomics reveals the mechanism of quercetin enhancing the bioavailability of ticagrelor

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