Development of a Ternary Solid Dispersion Formulation of LW6 to Improve the In Vivo Activity as a BCRP Inhibitor: Preparation and In Vitro/In Vivo Characterization

LW6 (3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester) is a potent inhibitor of drug efflux by the breast cancer resistance protein (BCRP). However, its poor aqueous solubility leads to low bioavailability, which currently limits in vivo applications. Therefore, the present study aimed to develop ternary solid dispersion (SD) formulations in order to enhance the aqueous solubility and dissolution rate of LW6. Various SDs of LW6 were prepared using a solvent evaporation method with different drug/excipient ratios. The solubility and dissolution profiles of LW6 in different SDs were examined, and F8-SD which is composed of LW6, poloxamer 407, and povidone K30 at a weight ratio of 1:5:8 was selected as the optimal SD. The structural characteristics of F8-SD were also examined using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and scanning electron microscopy (SEM). In the acidic to neutral pH range, F8-SD achieved rapid dissolution with a drug release of 76–81% within 20 min, while the dissolution of pure LW6 was negligible. The XRPD patterns indicated that F8-SD probably enhanced the solubility and dissolution of LW6 by changing the drug crystallinity to an amorphous state, in addition to the solubilizing effect of the hydrophilic carriers. Furthermore, F8-SD significantly improved the oral bioavailability of topotecan, which is a BCRP substrate, in rats. The systemic exposure of topotecan was enhanced approximately 10-fold by the concurrent use of F8-SD. In conclusion, the ternary SD formulation of LW6 with povidone K30 and poloxamer 407 appeared to be effective at improving the dissolution and in vivo effects of LW6 as a BCRP inhibitor.

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Preparation, characterization and evaluation of the in vivo trypanocidal activity of ursolic acid-loaded solid dispersion with poloxamer 407 and sodium caprate

Brazilian Journal of Pharmaceutical Sciences ◽

10.1590/s1984-82502015000100011 ◽

2015 ◽

Vol 51 (1) ◽

pp. 101-109 ◽

Cited By ~ 12

Author(s):

Josimar Oliveira Eloy ◽

Juliana Saraiva ◽

Sérgio de Albuquerque ◽

Juliana Maldonado Marchetti

Keyword(s):

Ursolic Acid ◽

Solid Dispersion ◽

Oral Absorption ◽

Solid Dispersions ◽

Poloxamer 407 ◽

Drug Dissolution ◽

Limiting Factors ◽

Sodium Caprate ◽

Trypanocidal Activity

Ursolic acid is a promising candidate for treatment of Chagas disease; however it has low aqueous solubility and intestinal absorption, which are both limiting factors for bioavailability. Among the strategies to enhance the solubility and dissolution of lipophilic drugs, solid dispersions are growing in popularity. In this study, we employed a mixture of the surfactants poloxamer 407 with sodium caprate to produce a solid dispersion containing ursolic acid aimed at enhancing both drug dissolution and in vivo trypanocidal activity. Compared to the physical mixture, the solid dispersion presented higher bulk density and smaller particle size. Fourier Transform Infrared Spectroscopy results showed hydrogen bonding intermolecular interactions between drug and poloxamer 407. X-ray diffractometry experiments revealed the conversion of the drug from its crystalline form to a more soluble amorphous structure. Consequently, the solubility of ursolic acid in the solid dispersion was increased and the drug dissolved in a fast and complete manner. Taken together with the oral absorption-enhancing property of sodium caprate, these results explained the increase of the in vivo trypanocidal activity of ursolic acid in solid dispersion, which also proved to be safe by cytotoxicity evaluation using the LLC-MK2 cell line.

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Design and Characterization of Phosphatidylcholine-Based Solid Dispersions of Aprepitant for Enhanced Solubility and Dissolution

Pharmaceutics ◽

10.3390/pharmaceutics12050407 ◽

2020 ◽

Vol 12 (5) ◽

pp. 407

Author(s):

Sooho Yeo ◽

Jieun An ◽

Changhee Park ◽

Dohyun Kim ◽

Jaehwi Lee

Keyword(s):

Solid Dispersion ◽

Solid Dispersions ◽

Amorphous State ◽

Aqueous Solubility ◽

Water Soluble ◽

Scanning Calorimetry ◽

Promising Alternative ◽

Dispersion System ◽

Enhanced Solubility ◽

Water Soluble Drugs

This study aimed to improve the solubility and dissolution of aprepitant, a drug with poor aqueous solubility, using a phosphatidylcholine (PC)-based solid dispersion system. When fabricating the PC-based solid dispersion, we employed mesoporous microparticles, as an adsorbent, and disintegrants to improve the sticky nature of PC and dissolution of aprepitant, respectively. The solid dispersions were prepared by a solvent evaporation technique and characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry, and X-ray powder diffraction. The FTIR results showed that aprepitant interacted with the PC carrier by both hydrogen bonds and van der Waals forces that can also be observed in the interaction between aprepitant and polymer carriers. The solid dispersions fabricated with only PC were not sufficient to convert the crystallinity of aprepitant to an amorphous state, whereas the formulations that included adsorbent and disintegrant successfully changed that of aprepitant to an amorphous state. Both the solubility and dissolution of aprepitant were considerably enhanced in the PC-based solid dispersions containing adsorbent and disintegrant compared with those of pure aprepitant and polymer-based solid dispersions. Therefore, these results suggest that our PC-based solid dispersion system is a promising alternative to conventional formulations for poorly water-soluble drugs, such as aprepitant.

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Enhanced dissolution and bioavailability of Nateglinide by microenvironmental pH-regulated ternary solid dispersion: in-vitro and in-vivo evaluation

Journal of Pharmacy and Pharmacology ◽

10.1111/jphp.12756 ◽

2017 ◽

Vol 69 (9) ◽

pp. 1099-1109 ◽

Cited By ~ 4

Author(s):

Sarika Wairkar ◽

Ram Gaud ◽

Namdeo Jadhav

Keyword(s):

Solid Dispersion ◽

In Vivo Evaluation ◽

Enhanced Dissolution ◽

Microenvironmental Ph ◽

Ternary Solid Dispersion

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FORMULATION AND OPTIMIZATION OF CURCUMIN SOLID DISPERSION PELLETS FOR IMPROVED SOLUBILITY

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2020v12i2.34846 ◽

2019 ◽

pp. 36-46

Author(s):

SANJEEVANI DESHKAR ◽

ARUN SATPUTE

Keyword(s):

Solid Dispersion ◽

Weight Ratio ◽

Poloxamer 407 ◽

Drug Dissolution ◽

In Vitro Dissolution ◽

Phase Solubility ◽

Dsc Studies ◽

Poorly Soluble ◽

Extrusion Spheronization

Objective: The present study was aimed at designing of solid dispersion based pellets of curcumin (Cu) for improving its solubility. Methods: Solid dispersion (SD) of Cu was prepared by the melt method using Poloxamer 407 (Pol 407) at a different weight ratio of Cu-Pol 407 (1:2, 1:3, 1:5, 1:7, 1:10). The solid dispersion was characterised by FTIR, SEM, DSC, XRD and evaluated for saturation solubility in water, drug content and in vitro dissolution. The pellets of Cu solid dispersion were prepared by extrusion spheronization technique and optimization was performed by 32full factorial design. The pellets were evaluated for size distribution, flow properties, hardness, disintegration and in vitro drug dissolution. Results: From the phase solubility analysis, Pol 407 was selected as a Solid dispersion carrier. The formation of Cu-SD by melt method using Pol 407, was confirmed from FTIR and DSC studies. XRD studies indicated a change of Cu from crystalline to amorphous form. There was a significant increase of Cu when formulated as SD compared to plain Cu. The optimization of extrusion spheronization process revealed the significant effect of Cu-Pol 407 ratio (p<0.0001) on in vitro dissolution of pellets. Higher Cu dissolution was obtained with Cu-SD pellets compared to plain Cu pellets. Conclusion: The present study demonstrated the potential of Cu-SD pellets in improving the solubility of poorly soluble Cu.

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Improved In vivo Effect of Chrysin as an Absorption Enhancer Via the Preparation of Ternary Solid Dispersion with Brij®L4 and Aminoclay

Current Drug Delivery ◽

10.2174/1567201815666180924151458 ◽

2018 ◽

Vol 16 (1) ◽

pp. 86-92 ◽

Cited By ~ 5

Author(s):

Sang Hoon Lee ◽

Yeo-song Lee ◽

Jae Geun Song ◽

Hyo-Kyung Han

Keyword(s):

Drug Release ◽

Drug Carrier ◽

Solid Dispersions ◽

Amorphous State ◽

Absorption Enhancer ◽

Cancer Resistance ◽

Surface Acting ◽

Strong Inhibitor

Background: Chrysin is a strong inhibitor of breast cancer resistance protein (BCRP) but it is practically insoluble in water. Effective solubilization of chrysin is critical for its pharmaceutical application as an absorption enhancer via inhibition of BCRP-mediated drug efflux. Objective: This study aimed to develop an effective oral formulation of chrysin to improve its in vivo effect as an absorption enhancer. Method: Solid dispersions (SDs) of chrysin were prepared with hydrophilic carriers having surface acting properties and a pH modulator. In vitro and in vivo characterizations were performed to select the optimal SDs of chrysin. Results: SDs with Brij&®L4 and aminoclay was most effective in increasing the solubility of chrysin by 13-53 fold at varying drug-carrier ratios. Furthermore, SDs significantly improved the dissolution rate and extent of drug release. SDs (chrysin: Brij&®L4: aminoclay=1:3:5) achieved approximately 60% and 83% drug release within 1 h and 8 h, respectively, in aqueous medium, while the dissolution of the untreated chrysin was less than 13%. XRD patterns indicated the amorphous state of chrysin in SDs. The SD formulation was effective in improving the bioavailability of topotecan, a BCRP substrate in rats. Following oral administration of topotecan with the SDs of chrysin, the Cmax and AUC of topotecan was enhanced by approximately 2.6- and 2-fold, respectively, while the untreated chrysin had no effect. Conclusion: The SD formulation of chrysin with Brij&®L4 and aminoclay appeared to be promising in improving the dissolution of chrysin and enhancing its in vivo effect as an absorption enhancer.

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Formulation and Characterization of Solid Dispersion Containing Capsaicin for the Treatment of Diabetes

Current Drug Therapy ◽

10.2174/1574885514666190916152432 ◽

2020 ◽

Vol 15 (3) ◽

pp. 219-225

Author(s):

Tapan Kumar Giri ◽

Payel Roy ◽

Subhasis Maity

Keyword(s):

Thermal Analysis ◽

Differential Thermal Analysis ◽

Animal Study ◽

Solid Dispersion ◽

Solid Dispersions ◽

Aqueous Solubility ◽

Peg 6000 ◽

X Ray

Background: Chili peppers are widely used in many cuisines as a spice, and capsaicin is the main component. It has been reported that capsaicin acts as an antihyperglycemic agent. However, it shows poor aqueous solubility and bioavailability. Objective: The is to enhance the aqueous solubility and antihyperglycemic activity of capsaicin through solid dispersion formulation. Methods: Solid dispersions were prepared by the solvent evaporation method using polyethylene glycol 6000 (PEG 6000) as a hydrophilic carrier. Polymer-drug miscibility and drug crystallinity were characterized through the differential thermal analysis and X-ray powder patterns analysis. Solid dispersions were evaluated for solubility, in vitro drug dissolution and in vivo animal study in rats. Results: Results of x-ray powder patterns analysis showed a considerable reduction of drug crystallinity in solid dispersion. Differential thermal analysis result revealed a complete disappearance of capsaicin melting onset temperature in solid dispersion. From the phase solubility data, it was observed that the aqueous solubility of capsaicin was increased with increasing concentration of PEG 6000. Solid dispersion formulation showed considerable enhancement of in vitro release of drugs in comparison to pure capsaicin. In vivo animal study in rats shows that the solid dispersion containing capsaicin significantly reduced the blood glucose level in comparison to the free capsaicin. Conclusion: Higher anti-hyperglycemic effect of capsaicin loaded solid dispersion in comparison to the pure drug may be due to the enhancement of aqueous solubility of capsaicin. Thus, the solid dispersion of capsaicin showed a simple approach for capsaicin delivery with improved antidiabetic activity.

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Ternary Solid Dispersion Strategy for Solubility Enhancement of Poorly Soluble Drugs by Co-Milling Technique

10.5772/intechopen.95518 ◽

2021 ◽

Author(s):

Marouene Bejaoui ◽

Hanen Oueslati ◽

Haykel Galai

Keyword(s):

Solid Dispersion ◽

Drug Carrier ◽

Water Soluble ◽

Pharmaceutical Ingredients ◽

Drug Molecules ◽

Water Soluble Drugs ◽

Milling Method ◽

Ternary Solid Dispersion

Amorphous ternary solid dispersion has become one of the strategies commonly used for improving the solubility and bioavailability of poorly water soluble drugs. Such multicomponent solid dispersion can be obtained by different techniques, this chapter provides an overview of ternary solid dispersion by co-milling method from the perspectives of physico-chemical characteristics in vitro and in vivo performance. A considerable improvement of solubility was obtained for many active pharmaceutical ingredients (e.g., Ibuprofen, Probucol, Gliclazid, Fenofibrate, Ibrutinib and Naproxen) and this was correlated to the synergy of multiple factors (hydrophilicity enhancement, particle size reduction, drug-carrier interactions, anti-plasticizing effect and complexation efficiency). This enhanced pharmacokinetic properties and bioavailability of these drug molecules (1.49 to 15-folds increase in plasma drug concentration). A particular focus was accorded to compare the ternary and binary system including Ibuprofen and highlighting the contribution of thermal and spectral characterization techniques. The addition of polyvinylpyrrolidone (PVP K30), a low molecular weight molecule, into the binary solid dispersion (Ibuprofen/β-cyclodextrin), leads to a 1.5–2 folds increase in the drug intrinsic dissolution rate only after 10 min. This resulted from physical stabilization of amorphous Ibuprofen by reducing its molecular mobility and inhibiting its recristallization even under stress conditions (75% RH and T = 40°C for six months).

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