Amorphous solid dispersions of enzalutamide and novel polysaccharide derivatives: investigation of relationships between polymer structure and performance

Abstract Amorphous solid dispersion (ASD) is a widely employed formulation technique for drugs with poor aqueous solubility. Polymers are integral components of ASDs, but mechanisms by which polymers lead to the generation and maintenance of supersaturated solutions, which enhance oral absorption in vivo, are poorly understood. Herein, a diverse group of newly synthesized cellulose derivatives was evaluated for their ability to inhibit crystallization of enzalutamide, a poorly soluble compound used to treat prostate cancer. ASDs were prepared from selected polymers, specifically a somewhat hydrophobic polymer that was extremely effective at inhibiting drug crystallization, and a less effective, but more hydrophilic, crystallization inhibitor, that might afford better release. Drug membrane transport rate was evaluated in vitro and compared to in vivo performance, following oral dosing in rats. Good correlation was noted between the in vitro diffusion cell studies and the in vivo data. The ASD formulated with the less effective crystallization inhibitor outperformed the ASD prepared with the highly effective crystallization inhibitor in terms of the amount and rate of drug absorbed in vivo. This study provides valuable insight into key factors impacting oral absorption from enabling ASD formulations, and how best to evaluate such formulations using in vitro approaches.

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Fenofibrate Solid Dispersion for Improving Oral Bioavailability: Preparation, and Characterization and in vivo Evaluation

International Journal of Pharmaceutical Sciences and Nanotechnology ◽

10.37285/ijpsn.2020.13.5.7 ◽

2020 ◽

Vol 13 (5) ◽

pp. 5102-5109

Author(s):

Venu Madhav K ◽

Somnath De ◽

Chandra Shekar Bonagiri ◽

Sridhar Babu Gummadi

Keyword(s):

Oral Bioavailability ◽

Oral Delivery ◽

Solid Dispersions ◽

In Vitro Release ◽

Aqueous Solubility ◽

Water Soluble ◽

Scanning Calorimetry ◽

In Vivo Evaluation

Fenofibrate (FN) is used in the treatment of hypercholesterolemia. It shows poor dissolution and poor oral bioavailability after oral administration due to high liphophilicity and low aqueous solubility. Hence, solid dispersions (SDs) of FN (FN-SDs) were develop that might enhance the dissolution and subsequently oral bioavailability. FN-SDs were prepared by solvent casting method using different carriers (PEG 4000, PEG 6000, β cyclodextrin and HP β cyclodextrin) in different proportions (0.25%, 0.5%, 0.75% and 1% w/v). FN-SDs were evaluated solubility, assay and in vitro release studies for the optimization of SD formulation. Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM) analysis was performed for crystalline and morphology analysis, respectively. Further, optimized FN-SD formulation evaluated for pharmacokinetic performance in Wistar rats, in vivo in comparison with FN suspension. From the results, FN-SD3 and FN-SD6 have showed 102.9 ±1.3% and 105.5±3.1% drug release, respectively in 2 h. DSC and PXRD studies revealed that conversion of crystalline to amorphous nature of FN from FT-SD formulation. SEM studies revealed the change in the orientation of FN when incorporated in SDs. The oral bioavailability FN-SD3 and FN-SD6 formulations exhibited 2.5-folds and 3.1-folds improvement when compared to FN suspension as control. Overall, SD of FN could be considered as an alternative dosage form for the enhancement of oral delivery of poorly water-soluble FN.

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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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Progress to Improve Oral Bioavailability and Beneficial Effects of Resveratrol

International Journal of Molecular Sciences ◽

10.3390/ijms20061381 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1381 ◽

Cited By ~ 50

Author(s):

Adele Chimento ◽

Francesca De Amicis ◽

Rosa Sirianni ◽

Maria Sinicropi ◽

Francesco Puoci ◽

...

Keyword(s):

Solid Dispersions ◽

Aqueous Solubility ◽

In Vivo Studies ◽

Beneficial Effects ◽

Lipid Nanocarriers ◽

Methodological Approaches ◽

Neuroprotective Actions ◽

Synthetic Derivatives

Resveratrol (3,5,4′-trihydroxystilbene; RSV) is a natural nonflavonoid polyphenol present in many species of plants, particularly in grapes, blueberries, and peanuts. Several in vitro and in vivo studies have shown that in addition to antioxidant, anti-inflammatory, cardioprotective and neuroprotective actions, it exhibits antitumor properties. In mammalian models, RSV is extensively metabolized and rapidly eliminated and therefore it shows a poor bioavailability, in spite it of its lipophilic nature. During the past decade, in order to improve RSV low aqueous solubility, absorption, membrane transport, and its poor bioavailability, various methodological approaches and different synthetic derivatives have been developed. In this review, we will describe the strategies used to improve pharmacokinetic characteristics and then beneficial effects of RSV. These methodological approaches include RSV nanoencapsulation in lipid nanocarriers or liposomes, nanoemulsions, micelles, insertion into polymeric particles, solid dispersions, and nanocrystals. Moreover, the biological results obtained on several synthetic derivatives containing different substituents, such as methoxylic, hydroxylic groups, or halogens on the RSV aromatic rings, will be described. Results reported in the literature are encouraging but require additional in vivo studies, to support clinical applications.

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Microencapsulation of amorphous solid dispersions of fenretinide enhances drug solubility and release from PLGA in vitro and in vivo

International Journal of Pharmaceutics ◽

10.1016/j.ijpharm.2020.119475 ◽

2020 ◽

Vol 586 ◽

pp. 119475 ◽

Cited By ~ 3

Author(s):

Kari Nieto ◽

Susan R. Mallery ◽

Steven P. Schwendeman

Keyword(s):

Solid Dispersions ◽

Amorphous Solid ◽

Drug Solubility ◽

Amorphous Solid Dispersions

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Systemic in vitro and in vivo evaluation for determining the feasibility of making an amorphous solid dispersion of a B-Raf (rapidly accelerated fibrosarcoma) inhibitor

International Journal of Pharmaceutics ◽

10.1016/j.ijpharm.2013.06.064 ◽

2013 ◽

Vol 454 (1) ◽

pp. 241-248 ◽

Cited By ~ 8

Author(s):

Yong Cui ◽

Po-Chang Chiang ◽

Edna F. Choo ◽

Jason Boggs ◽

Joachim Rudolph ◽

...

Keyword(s):

Solid Dispersion ◽

Amorphous Solid ◽

Amorphous Solid Dispersion ◽

In Vivo Evaluation

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Amorphous solid dispersions and the confounding effect of nanoparticles in in vitro dissolution and in vivo testing: Niclosamide as a case of study

10.1101/2020.12.22.424004 ◽

2020 ◽

Author(s):

Miguel O Jara ◽

Zachary N Warnken ◽

Robert O Williams

Keyword(s):

Amorphous Solid ◽

Fold Increase ◽

Water Soluble ◽

In Vitro Dissolution ◽

Amorphous Solid Dispersion ◽

In Vitro Tests ◽

Manufacturing Method ◽

Poorly Water Soluble

We developed an amorphous solid dispersion (ASD) of the poorly water soluble molecule niclosamide that achieved more than a 2 fold increase in bioavailability. Notably, this niclosamide ASD formulation increased the apparent drug solubility about 60 fold relative to the crystalline material due to the generation of nanoparticles. Niclosamide is a weakly acidic drug, BCS class II, and a poor glass former with low bioavailability in vivo. Hot melt extrusion is a high throughput manufacturing method commonly used in the development of ASDs for increasing the apparent solubility and bioavailability of poorly water-soluble compounds. We utilized the polymer polyvinylpyrrolidone vinyl acetate (PVPVA) to manufacture niclosamide ASDs by extrusion. Samples were analyzed based on their microscopic and macroscopic behavior and their intermolecular interactions, using DSC, XRD, NMR, FTIR, and DLS. The niclosamide ASD generated nanoparticles with a mean particle size of about 100 nm in FaSSIF media. In a side by side diffusion test, these nanoparticles produced a 4 fold increase in niclosamide diffusion. We successfully manufactured amorphous extrudates of the poor glass former niclosamide that showed remarkable in vitro dissolution and diffusion performance. These in vitro tests were translated to a rat model that also showed an increase in oral bioavailability.

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Spray-Dried Amorphous Solid Dispersions of Atorvastatin Calcium for Improved Supersaturation and Oral Bioavailability

Pharmaceutics ◽

10.3390/pharmaceutics11090461 ◽

2019 ◽

Vol 11 (9) ◽

pp. 461 ◽

Cited By ~ 9

Author(s):

Kwon ◽

Giri ◽

Song ◽

Bae ◽

Lee ◽

...

Keyword(s):

Spray Drying ◽

Solid Dispersions ◽

Amorphous Solid ◽

Aqueous Solubility ◽

Free Drug ◽

Lipid Lowering ◽

Amorphous Solid Dispersions ◽

Atorvastatin Calcium ◽

Promising Strategy

Over the past few decades, the amorphous solid dispersions (ASDs) technique has emerged as a promising strategy to enhance the in vitro/in vivo characteristic of hydrophobic drugs. The low aqueous solubility and poor bioavailability of atorvastatin calcium (ATO), a lipid-lowering drug, present challenges for effective drug delivery. The objective of this work was to improve the aqueous solubility, in vitro dissolution, and oral absorption of ATO with amorphous solid dispersion technique prepared by spray-drying method. The optimized ternary formulation comprising of ATO; hydroxypropyl methylcellulose (HPMC), as a hydrophilic polymer; and sodium lauryl sulfate (SLS), as a surfactant, at a weight ratio of 1/1/0.1, showed significant improvement in aqueous solubility by ~18-fold compared to that of the free drug, and a cumulative release of 94.09% compared to a release of 59.32% of the free drug. Further, physicochemical studies via scanning electron microscopy, differential scanning calorimetry, and powder X-ray diffraction revealed a change from the crystalline state of the free drug to its amorphous state in the ASD. Pharmacokinetic analysis in rats demonstrated 1.68- and 2.39-fold increments in AUC and Cmax, respectively, in the ASD over the free drug. Altogether, hydrophilic carrier-based ASDs prepared by the spray-drying technique represent a promising strategy to improve the biopharmaceutical performance of poorly soluble drugs.

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Preparation and Characterization of Spherical Amorphous Solid Dispersion with Amphotericin B

Pharmaceutics ◽

10.3390/pharmaceutics10040235 ◽

2018 ◽

Vol 10 (4) ◽

pp. 235 ◽

Cited By ~ 10

Author(s):

Lyes Mehenni ◽

Malika Lahiani-Skiba ◽

Guy Ladam ◽

François Hallouard ◽

Mohamed Skiba

Keyword(s):

Amphotericin B ◽

Solid Dispersion ◽

In Vitro Release ◽

Amorphous Solid ◽

Amorphous Solid Dispersion ◽

Scanning Calorimetry ◽

New Generation ◽

Powder Aerosols

In the present study, new polymer microspheres of amphotericin B (AmB) were prepared by a spray drying technique using cyclodextrin polymers (Poly-CD) to improve the solubility and dissolution of AmB, to prevent in vivo toxic AmB aggregations. Formulations were characterized through scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), thermal analysis, Raman spectroscopy, particle size, drug purity test and in vitro release studies. The analysis indicated that the chemical structure of AmB remained unchanged in the amorphous solid dispersion, but the structure was changed from crystalline to amorphous. AmB was completely release from such optimized formulations in dissolution media in 40 min. This work may contribute to a new generation of spherical amorphous solid dispersion using a cyclodextrin polymer, which has implications for the possibility of drug development for oral utilization or as powder aerosols for pulmonary administration.

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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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