Mechanochemical preparation of chrysomycin A self-micelle solid dispersion with improved solubility and enhanced oral bioavailability

Abstract Background Chrysomycin A (CA) has been reported as numerous excellent biological activities, such as antineoplastic and antibacterial. Though, poor solubility of CA limited its application in medical field. Due to good amphiphilicity and potential anticancer effect of disodium glycyrrhizin (Na2GA) as an excipient, an amorphous solid dispersion (Na2GA/CA-BM) consisting of CA and Na2GA was prepared in the present study by mechanochemical technology (roll mill ML-007, zirconium balls, 30 rpm, 2.5 h) to improve the solubility and oral bioavailability of CA. Then, Na2GA/CA-BM was self-assembled to micelles in water. The interaction of CA and Na2GA in solid state were investigated by X-ray diffraction studies, polarized light microscopy, and scanning electron microscope. Meanwhile, the properties of the sample solution were analyzed by dynamic light scattering and transmission electron. Furthermore, the oral bioavailability and antitumor ability of Na2GA/CA-BM in vivo were tested, providing a theoretical basis for future application of CA on cancer therapy. Results CA encapsulated by Na2GA was self-assembled to nano-micelles in water. The average diameter of nano-micelle was 131.6 nm, and zeta potential was − 11.7 mV. Three physicochemical detections showed that CA was transformed from crystal into amorphous form after treated with ball milling and the solubility increased by 50 times. Na2GA/CA-BM showed a significant increase of the bioavailability about two time that of free CA. Compared with free CA, the in-vivo antitumor studies also exhibited that Na2GA/CA-BM had an excellent inhibition of tumor growth. Conclusions Na2GA/CA-BM nanoparticles (131.6 nm, − 11.7 mV) prepared by simple and low-cost mechanochemical technology can improve oral bioavailability and antitumor efficacy of CA in vivo, suggesting a potential formulation for efficient anticancer treatment. Graphic abstract

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Mechanochemical preparation of chrysomycin A self-micelle solid dispersion with improved solubility and enhanced oral bioavailability

10.21203/rs.3.rs-286030/v1 ◽

2021 ◽

Author(s):

Zhuomin Xu ◽

Shanshan Zheng ◽

Yulu Hong ◽

Yue Cai ◽

Qiuqin Zhang ◽

...

Keyword(s):

Solid Dispersion ◽

Oral Bioavailability ◽

Biological Activities ◽

Low Cost ◽

Polarized Light ◽

Average Diameter ◽

Future Application ◽

Amorphous Solid Dispersion ◽

Self Assembled

Abstract Background: Chrysomycin A (CA) has been reported as numerous excellent biological activities, such as antineoplastic and antibacterial. Though, poor solubility of CA limited its application in medical field. Due to good amphiphilicity and potential anticancer effect of disodium glycyrrhizin (Na2GA) as an excipient, an amorphous solid dispersion (Na2GA/CA-BM) consisting of CA and Na2GA was prepared in the present study by mechanochemical technology (roll mill ML-007, zirconium balls, 30 rpm, 2.5 h) to improve the solubility and oral bioavailability of CA. Then, Na2GA/CA-BM was self-assembled to micelles in water. The interaction of CA and Na2GA in solid state were investigated by X-ray diffraction studies, polarized light microscopy, and scanning electron microscope. Meanwhile, the properties of the sample solution were analyzed by dynamic light scattering and transmission electron. Furthermore, the oral bioavailability and antitumor ability of Na2GA/CA-BM in vivo were tested, providing a theoretical basis for future application of CA on cancer therapy.Results: CA encapsulated by Na2GA was self-assembled to nano-micelles in water. The average diameter of nano-micelle was 131.6 nm, and zeta potential was -11.7 mV. Three physicochemical detections showed that CA was transformed from crystal into amorphous form after treated with ball milling and the solubility increased by 50 times. Na2GA/CA-BM showed a significant increase of the bioavailability about 2 time that of free CA. Compared with free CA, the in-vivo antitumor studies also exhibited that Na2GA/CA-BM had an excellent inhibition of tumor growth.Conclusions: Na2GA/CA-BM nanoparticles (131.6 nm, -11.7 mV) prepared by simple and low-cost mechanochemical technology can improve oral bioavailability and antitumor efficacy of CA in vivo, suggesting a potential formulation for efficient anticancer treatment.

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Effect of surfactant on the in vitro dissolution and the oral bioavailability of a weakly basic drug from an amorphous solid dispersion

European Journal of Pharmaceutical Sciences ◽

10.1016/j.ejps.2021.105836 ◽

2021 ◽

pp. 105836

Author(s):

Nguyen-Thach Tung ◽

Cao-Son Tran ◽

Tran-Linh Nguyen ◽

Thi-Minh-Hue Pham ◽

Sang-Cheol Chi ◽

...

Keyword(s):

Solid Dispersion ◽

Oral Bioavailability ◽

Amorphous Solid ◽

In Vitro Dissolution ◽

Amorphous Solid Dispersion ◽

Basic Drug

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Efficient Development of Sorafenib Tablets with Improved Oral Bioavailability Enabled by Coprecipitated Amorphous Solid Dispersion

International Journal of Pharmaceutics ◽

10.1016/j.ijpharm.2021.121216 ◽

2021 ◽

pp. 121216

Author(s):

Sichen Song ◽

Chenguang Wang ◽

Shan Wang ◽

Ronald A. Siegel ◽

Changquan Calvin Sun

Keyword(s):

Solid Dispersion ◽

Oral Bioavailability ◽

Amorphous Solid ◽

Amorphous Solid Dispersion

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Relationship between amorphous solid dispersion in vivo absorption and in vitro dissolution: phase behavior during dissolution, speciation, and membrane mass transport

Journal of Controlled Release ◽

10.1016/j.jconrel.2018.11.003 ◽

2018 ◽

Vol 292 ◽

pp. 172-182 ◽

Cited By ~ 46

Author(s):

Venecia Wilson ◽

Xiaochun Lou ◽

Donald J. Osterling ◽

Deanne F. Stolarik ◽

Gary Jenkins ◽

...

Keyword(s):

Mass Transport ◽

Phase Behavior ◽

Solid Dispersion ◽

Amorphous Solid ◽

In Vitro Dissolution ◽

Amorphous Solid Dispersion ◽

In Vivo Absorption

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Enhanced Oral Bioavailability and Improved Biological Activities of a Quercetin/Resveratrol Combination Using a Liquid Self-Microemulsifying Drug Delivery System

Planta Medica ◽

10.1055/a-1270-7606 ◽

2020 ◽

Author(s):

Patcharawalai Jaisamut ◽

Subhaphorn Wanna ◽

Surasak Limsuwan ◽

Sasitorn Chusri ◽

Kamonthip Wiwattanawongsa ◽

...

Keyword(s):

Drug Delivery ◽

Drug Delivery System ◽

Delivery System ◽

Oral Bioavailability ◽

Biological Activities ◽

Area Under The Curve ◽

Aqueous Solubility ◽

The Self

AbstractBoth quercetin and resveratrol are promising plant-derived compounds with various well-described biological activities; however, they are categorized as having low aqueous solubility and labile natural compounds. The purpose of the present study was to propose a drug delivery system to enhance the oral bioavailability of combined quercetin and resveratrol. The suitable self-microemulsifying formulation containing quercetin together with resveratrol comprised 100 mg Capryol 90, 700 mg Cremophor EL, 200 mg Labrasol, 20 mg quercetin, and 20 mg resveratrol, which gave a particle size of 16.91 ± 0.08 nm and was stable under both intermediate and accelerated storage conditions for 12 months. The percentages of release for quercetin and resveratrol in the self-microemulsifying formulation were 75.88 ± 1.44 and 86.32 ± 2.32%, respectively, at 30 min. In rats, an in vivo pharmacokinetics study revealed that the area under the curve of the self-microemulsifying formulation containing quercetin and resveratrol increased approximately ninefold for quercetin and threefold for resveratrol compared with the unformulated compounds. Moreover, the self-microemulsifying formulation containing quercetin and resveratrol slightly enhanced the in vitro antioxidant and cytotoxic effects on AGS, Caco-2, and HT-29 cells. These findings demonstrate that the self-microemulsifying formulation containing quercetin and resveratrol could successfully enhance the oral bioavailability of the combination of quercetin and resveratrol without interfering with their biological activities. These results provide valuable information for more in-depth research into the utilization of combined quercetin and resveratrol.

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In vitro and in vivo activities of flavonoids – apigenin, baicalin, chrysin, scutellarin – in regulation of hypertension – a review for their possible effects in pregnancy-induced hypertension

Herba Polonica ◽

10.2478/hepo-2019-0001 ◽

2019 ◽

Vol 65 (1) ◽

pp. 55-70 ◽

Cited By ~ 1

Author(s):

Marcin Ożarowski ◽

Radosław Kujawski ◽

Przemysław Ł. Mikołajczak ◽

Karolina Wielgus ◽

Andrzej Klejewski ◽

...

Keyword(s):

Ex Vivo ◽

Biological Activities ◽

Wide Spectrum ◽

Chemical Compounds ◽

New Drugs ◽

Future Application ◽

Mediators Of Inflammation ◽

And Function

Summary Flavonoids and their conjugates are the most important group of natural chemical compounds in drug discovery and development. The search for pharmacological activity and new mechanisms of activity of these chemical compounds, which may inhibit mediators of inflammation and influence the structure and function of endothelial cells, can be an interesting pharmacological strategy for the prevention and adjunctive treatments of hypertension, especially induced by pregnancy. Because cardiovascular diseases have multi-factorial pathogenesis these natural chemical compounds with wide spectrum of biological activities are the most interesting source of new drugs. Extracts from one of the most popular plant used in Traditional Chinese Medicine, Scutellaria baicalensis Georgi could be a very interesting source of flavonoids because of its exact content in quercetin, apigenin, chrysin and scutellarin as well as in baicalin. These flavonoids exert vasoprotective properties and many activities such as: anti-oxidative via several pathways, anti-in-flammatory, anti-ischaemic, cardioprotective and anti-hypertensive. However, there is lack of summaries of results of studies in context of potential and future application of flavonoids with determined composition and activity. Our review aims to provide a literature survey of in vitro, in vivo and ex vivo pharmacological studies of selected flavonoids (apigenin, chrysin and scutellarin, baicalin) in various models of hypertension carried out in 2008–2018.

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Enhanced Oral Bioavailability of Celecoxib Nanocrystalline Solid Dispersion based on Wet Media Milling Technique: Formulation, Optimization and In Vitro/In Vivo Evaluation

Pharmaceutics ◽

10.3390/pharmaceutics11070328 ◽

2019 ◽

Vol 11 (7) ◽

pp. 328 ◽

Cited By ~ 9

Author(s):

Zhuang Ding ◽

Lili Wang ◽

Yangyang Xing ◽

Yanna Zhao ◽

Zhengping Wang ◽

...

Keyword(s):

Particle Size ◽

Zeta Potential ◽

Solid Dispersion ◽

Oral Bioavailability ◽

Stability Study ◽

Sprague Dawley ◽

Scanning Calorimetry ◽

In Vivo Evaluation

Celecoxib (CLX), a selective COX-2 inhibitor, is a biopharmaceutics classification system (BCS) class II drug with its bioavailability being limited by thepoor aqueoussolubility. The purpose of this study was to develop and optimize CLX nanocrystalline(CLX-NC) solid dispersion prepared by the wet medium millingtechnique combined with lyophilizationto enhance oral bioavailability. In formulation screening, the resulting CLX-NC usingpolyvinylpyrrolidone (PVP) VA64 and sodiumdodecyl sulfate (SDS) as combined stabilizers showed the minimum particle size and a satisfactory stability. The formulation and preparation processwere further optimized by central composite experimentaldesign with PVP VA64 concentration (X1), SDS concentration (X2) and milling times (X3) as independent factors and particle size (Y1), polydispersity index (PDI, Y2) and zeta potential (Y3) as response variables. The optimal condition was determined as a combination of 0.75% PVP VA64, 0.11% SDS with milling for 90 min.The particle size, PDI and zeta potential of optimized CLX-NC were found to be 152.4 ± 1.4 nm, 0.191 ± 0.012 and −34.4 ± 0.6 mV, respectively. The optimized formulation showed homogeneous rod-like morphology as observed by scanning electron microscopy and was in a crystalline state as determined by differential scanning calorimetry and powder X-ray diffraction. In a storage stability study, optimized CLX-NC exhibited an excellent physical stability during six months’ storage at both the refrigeration and room conditions. In vivo pharmacokinetic research in Sprague-Dawley ratsdisplayed that Cmax and AUC0–∞ of CLX-NC were increased by 2.9 and 3.1 fold, compared with physical mixture. In this study, the screening and optimizing strategy of CLX-NC formulation represents a commercially viable approach forenhancing the oral bioavailability of CLX.

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Oral Bioavailability Enhancement and Anti-Fatigue Assessment of the Andrographolide Loaded Solid Dispersion

International Journal of Molecular Sciences ◽

10.3390/ijms21072506 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2506 ◽

Cited By ~ 1

Author(s):

Ching-Chi Yen ◽

Yu-Kai Liang ◽

Chao-Pei Cheng ◽

Mei-Chich Hsu ◽

Yu-Tse Wu

Keyword(s):

Dissolution Rate ◽

Solid Dispersion ◽

Oral Bioavailability ◽

Water Solubility ◽

Biological Activities ◽

Wide Spectrum ◽

Amorphous State ◽

Vehicle Group ◽

Time To Exhaustion ◽

Pharmacokinetic Studies

Andrographolide (AG), a major diterpene lactone isolated from Andrographis paniculata (Burm. f.) Nees (Acanthaceae), possesses a wide spectrum of biological activities. However, its poor water solubility and low bioavailability limit its clinical application. Therefore, this study aimed to develop a solid dispersion (SD) formulation to increase the aqueous solubility and dissolution rate of AG. Different drug-polymer ratios were used to prepare various SDs. The optimized formulation was characterized for differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder X-ray diffraction. The analysis indicated that the optimized SD enhanced AG solubility and dissolution rates by changing AG crystallinity to an amorphous state. The dissolution behaviors of the optimum SD composed of an AG-polyvinylpyrrolidone K30-Kolliphor EL ratio of 1:7:1 (w/w/w) resulted in the highest accumulated dissolution (approximately 80%). Pharmacokinetic studies revealed that Cmax/dose and the AUC/dose increased by 3.7-fold and 3.0-fold, respectively, compared with AG suspension. Furthermore, pretreatment using the optimized AG-SD significantly increased the swimming time to exhaustion by 1.7-fold and decreased the plasma ammonia level by 71.5%, compared with the vehicle group. In conclusion, the optimized AG-SD formulation appeared to effectively improve its dissolution rate and oral bioavailability. Moreover, the optimized AG-SD provides a promising treatment against physical fatigue.

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