Improved Dissolution Behavior Research Articles

Raspberry ketone loaded self nanoemulsifying system of cardamom oil: Assessment of phase behavior, dissolution rate and anti-hyperlipidemic activity

Raspberry ketone (RK), a polyphenolic antioxidant, possesses free radical scavenging against oxidative species and has potential of anti-inflammatory, anti-proliferative and anti-aging activities. Major pharmaceutical restriction associated with RK is its poor dissolution characteristic owing to its hydrophobic nature. Present investigation is an attempt to improve dissolution behavior of RK using cardamom oil (CO) based self nanoemulsifying system (SNE) design and preclinical assessed for anti-hyperlipidemic activity. Demarcation of phase boundaries to exactly locate nanoemulsion areas were explored using ternary plots drawn between CO as oil phase, Tween 80/PEG 600 as Smix at 1:1; 1:2; 2:1 and 3:1 ratios. Previously ternary components were selected on the basis of solubility of RK and aqueous dispersibility of CO. Nanoemulsion areas developed under ternary phase region were quantified using trapezoidal method and found in the order 1:1 > 1:2 > 3:1 > 2:1 of Smix. Aqueous dilutibility of SNEs followed the pattern of dilutions lines drawn across the ternary phase and its interference. Optimized SNE produced 97.1 % transmittance with average droplet size 101 nm, zeta potential −2.27 mV and 0.186 mS/cm conductivity. In-vitro RK release was examined in HCl buffer at pH 1.2 and phosphate buffer at pH 6.8 showed a significant difference in the RK dissolved (p < 0.01) compared to RK suspension (control F6). Optimized formulation (F3) at two doses level (RK loading of 80 and 160 mg/kg) vs. RK suspension (160 mg/kg) was pre-clinically administered for four weeks to assess anti-hyperlipidemic activity. Lipid profile markers (levels of VLDL, HDL, LDL, total triglyceride and total cholesterol) were significantly reduced from nanoemulsion formulation as compared to its suspension. SNE formulations were stable with no appreciable loss in quality and performance for six month storage at 30 ± 2 °C; 65 ± 5 % RH conditions. CO based SNE design significantly extended the ternary area for nanoemulsion development as well as RK solubility; which in turn improved dissolution rate of RK and showed anti-hyperlipidemic activity.

Febuxostat ternary inclusion complex using SBE7-βCD in presence of a water-soluble polymer: physicochemical characterization, in vitro dissolution, and in vivo evaluation

Febuxostat (FBX), a potent xanthine oxidase inhibitor, is widely used as a blood uric acid-reducing agent and has recently shown a promising repurposing outcome as an anti-cancer. FBX is known for its poor water solubility, which is the main cause of its weak oral bioavailability. In a previous study, we developed a binary system complex between FBX and sulfobutylether-β-cyclodextrin (SBE7-βCD) with improved dissolution behavior. The aim of the current study was to investigate the effect of incorporating a water-soluble polymer with a binary system forming a ternary one, on further enhancement of FBX solubility and dissolution rate. In vivo oral bioavailability was also studied using LC–MS/MS chromatography. The polymer screening study revealed a marked increment in the solubility of FBX with SBE7-βCD in the presence of 5% w/v polyethylene glycol (PEG 6000). In vitro release profile showed a significant increase in the dissolution rate of FBX from FBX ternary complex (FTC). Oral in vivo bioavailability of prepared FTC showed more than threefold enhancement in Cmax value (17.05 ± 2.6 µg/mL) compared to pure FBX Cmax value (5.013 ± 0.417 µg/mL) with 257% rise in bioavailability. In conclusion, the association of water-soluble polymers with FBX and SBE7-βCD system could significantly improve therapeutic applications of the drug.Graphical

Solid lipid nanoparticles of lutein with improved dissolution behavior and oral absorption

The present study aimed to develop solid lipid nanoparticles of lutein (SLN/LT) with improved dissolution behavior and oral absorption. SLN/LT were prepared by a flash nanoprecipitation method using a multi-inlet vortex mixer, and their physicochemical, photochemical, and pharmacokinetic properties were evaluated. The mean particle size of SLN/LT re-dispersed in water was 237 nm, and small spherical particles with no significant aggregation were observed. LT significantly generated singlet oxygen upon exposure to pseudo-sunlight (250 W/m2, 1 h), suggesting its high photoreactivity. The remaining LT in LT solution, crystalline LT, and SLN/LT after irradiation with pseudo-sunlight (250 W/m2, 2 h) were 56.3, 86.7, and 101%, respectively. SLN/LT showed improved dissolution behavior of LT in simulated intestinal fluid, and the dissolved amounts of LT at 2 h were at least 50 times higher than that of crystalline LT. Orally administered SLN/LT (100 mg-LT/kg) exhibited enhanced oral absorption of LT, as evidenced by a relative bioavailability of 3.7 to crystalline LT in rats. SLN/LT may be a promising dosage form for orally available LT supplements, possibly leading to enhanced nutritional functions of LT.

Celecoxib-Loaded Self-micellizing Solid Dispersion Suppresses Its Delayed Absorption in Rats with Impaired Gastrointestinal Motility.

The aim of this study was to develop a self-micellizing solid dispersion of celecoxib (SMSD/CEL) with enhanced dissolution to suppress a delay in absorption under impairment of gastrointestinal (GI) secretion and motility induced by severe pain. Soluplus®-based SMSD/CEL was prepared by lyophilization and physiochemically characterized. A pharmacokinetic study of orally-dosed CEL samples was carried out in rats with propantheline (PPT)-induced the impairment of GI secretion and motility. SMSD/CEL was micellized in aqueous media with a mean diameter of 153 nm, and it showed improved dissolution behavior of CEL under acidic conditions with 2.1-fold higher dissolved CEL at 120 min than crystalline CEL. SMSD/CEL was found to be in an amorphous state, and there was no significant crystallization even after storage under accelerated conditions for 8 weeks, indicating relatively high storage stability of the amorphous form. Orally-dosed crystalline CEL in PPT-treated rats showed a delayed mean absorption time (MAT) and area under the curve of plasma concentration versus time from 0 to 4 h (AUC0-4) was reduced to 12% compared with that in normal rats, whereas SMSD/CEL suppressed the delay and decrease of absorption in PPT-treated rats. From these findings, SMSD/CEL might be efficacious to suppress poor and delayed absorption of CEL for better pain medication in the presence of impaired GI secretion and motility associated with severe pain.

Lysophosphatidylcholine-based liposome to improve oral absorption and nephroprotective effects of astaxanthin.

The present study was aimed to develop astaxanthin (AX)-loaded liposomes by the utilization of soybean phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) to improve the nutraceutical properties of AX. AX-loaded liposomes consisting of PC (PC/AX) and LPC (LPC/AX) were evaluated in terms of particle size distribution, morphology, release characteristics, pharmacokinetic behavior, and nephroprotective effects in a rat model of acute kidney injury. PC/AX and LPC/AX had uniform size distributions with a mean particle size of 254 and 148 nm, respectively. Under pH 6.8 conditions, both liposomes exhibited improved dissolution behavior of AX compared with crystalline AX (cAX). In particular, LPC/AX showed a sevenfold higher release of AX than PC/AX. After the oral administration of LPC/AX (33.2 mg AX kg-1 ) to rats, there was a significant increase in systemic exposure to AX, as evidenced by a 15-fold higher AUC0-24 h than PC/AX. However, the oral absorption of AX in the cAX group was negligible. Based on the results of histological analysis and measurement of plasma biomarkers, LPC/AX exhibited improved nephroprotective effects of AX in the rat model of kidney injury. From these observations, a strategic application of the LPC-based liposomal approach might be a promising option to improve the nutraceutical properties of AX. © 2022 Society of Chemical Industry.

Novel nano-crystalline solid dispersion of nobiletin with improved dissolution behavior and oral absorption

The present study aimed to develop a novel formulation of nobiletin (NOB, a citrus polymethoxylated flavone) by nano-crystalline solid dispersion (nCSD) approach for improving dissolution behavior and oral absorption. NOB-loaded nCSD (nCSD/NOB) was prepared by a wet-milling and freeze-drying systems. Physicochemical properties of nCSD/NOB were characterized in terms of crystallinity, dissolution behavior, particle size distribution, and surface morphology. An analytical method was developed and validated, and a pharmacokinetic study was conducted after oral administration of nCSD/NOB to rats. NOB particles in nCSD/NOB appeared to be crystalline, and the mean diameter was calculated to be ca. 120 nm. In water and acidic condition (pH 1.2), dissolution rates of NOB in nCSD/NOB were ca. 31- and 32-fold higher than those in crystalline NOB, respectively. After oral administration of nCSD/NOB (20 mg-NOB/kg) to rats, nCSD/NOB showed enhanced exposure of NOB compared with crystalline NOB, as evidenced by 12-fold increase of Cmax. The absolute oral bioavailability of NOB in nCSD/NOB was calculated to be ca. 13%, showing 15-fold enhancement compared with that in crystalline NOB. From these findings, the nCSD approach would be efficacious for improving oral absorption of NOB, leading to its enhanced nutraceutical potential.

Formulation and In Vitro Characterization of a Vacuum-Dried Drug-Polymer Thin Film for Intranasal Application.

Intranasal drug applications show significant therapeutic potential for diverse pharmaceutical modalities. Because the formulation applied to the nasal cavity is discharged to the pharyngeal side by mucociliary clearance, the formulation should be dissolved effectively in a limited amount of mucus within its retention time in the nasal cavity. In this study, to develop novel formulations with improved dissolution behavior and compatibility with the intranasal environment, a thin-film formulation including drug and polymer was prepared using a vacuum-drying method. The poorly water-soluble drugs ketoprofen, flurbiprofen, ibuprofen, and loxoprofen were dissolved in a solvent comprising water and methanol, and evaporated to obtain a thin film. Physical analyses using differential scanning calorimetry (DSC), powder X-ray diffraction analysis (PXRD), and scanning electron microscopy SEM revealed that the formulations were amorphized in the film. The dissolution behavior of the drugs was investigated using an in vitro evaluation system that mimicked the intranasal physiological environment. The amorphization of drugs formulated with polymers into thin films using the vacuum-drying method improved the dissolution rate in artificial nasal fluid. Therefore, the thin film developed in this study can be safely and effectively used for intranasal drug application.

Nanocrystals with different stabilizers overcome the mucus and epithelial barriers for oral delivery of multicomponent Bufadienolides

Using nanocrystals (NCs) technology may be a promising drug delivery strategy for oral administration of multicomponent anticancer drugs. However, the intestinal epithelium and the mucus layer on the intestine extremely limited drug transport and absorption by orally. In this study, we selected multicomponent inartificial compound Bufadienolides (BU) with broad spectrum antitumor activity as the model drug to prepare BU NCs with different stabilizers by wet grinding, and explored the efficiency of penetrating through the mucus layer and transporting intestinal epithelial cells in vitro and ex vivo. Results revealed that BU NCs can dramatically improve dissolution behavior synergistically and the efficiency of mucus permeation. Besides, we found that BU NCs with different stabilizers enhanced cellular uptake, which was mainly attributed to increasing or changing the endocytosis pathway and plasma membrane/Endoplasmic reticulum (ER) pathway involved in the transmembrane transport of NCs. Furthermore, BU NCs could definitely improve intestinal absorption efficiency and change the absorption site of BU ex vivo. This multi-angle exploration will provide reference for the development of BU oral delivery formulations.

Tranilast-loaded amorphous solid dispersion prepared with fine droplet drying process for improvement of oral absorption and anti-inflammatory effects on chemically-induced colitis

The aim of the present study was to evaluate the applicability of a tranilast (TL)-loaded amorphous solid dispersion prepared with a fine droplet drying (FDD) process for the treatment of inflammatory bowel diseases. The FDD process, a novel powderization technology using an inkjet head, was employed to produce an amorphous solid dispersion of tranilast (ASD/TL). The physicochemical properties of ASD/TL were evaluated in terms of the morphology, particle size, crystallinity, drug-polymer interaction, and dissolution behavior. The oral absorption behavior of TL and anti-inflammatory effect on a chemically-induced colitis model were evaluated after oral administration of TL samples. The particle size of ASD/TL was 4 μm, and the span factor, one of the parameters to present the uniformity of particle size distribution, was calculated to be 0.28. In each ASD/TL particle, TL was dispersed in an amorphous state in the carrier polymer, and ASD/TL showed improved dissolution behavior of TL, as evidenced by a 2-times higher dissolution than the equilibrium solubility of crystalline TL even under acidic conditions. Orally-dosed ASD/TL exhibited rapid and improved oral absorption with 16-fold higher bioavailability than crystalline TL. ASD/TL could significantly attenuate the inflammatory symptoms in the colon tissues of colitis model rats based on the results of histological analyses and measurement of biomarkers. ASD/TL might contribute to the development of effective treatment for inflammatory bowel diseases due to its enhanced biopharmaceutical properties.

Formulation of Eutectic mixture of Curcumin with Salicylic Acid for improving its Dissolution Profile

Background: Eutectics are basically multi-component crystalline solids closely related to solid solutions. However, the structural organization of eutectics has not been studied in as much detail as solid solutions, which are defined based on the arrangement of a major (solvent) and a minor (solute) component in the crystal lattice. Purpose: The goal of this study is basically improvement in aqueous solubility of poorly water soluble drug i.e curcumin via its eutectic formation by using salicylic acid as coformer. Material and Method: Here the eutectic mixture of curcumin and salicylic acid was prepared by solvent evaporation technique for improving the dissolution behaviour of curcumin. DSC and FT-IR spectroscopy were used as analytical techniques for characterization of eutectic mixture. Result: The DSC and FT-IR spectroscopy conformed the formation of eutectic mixture and In-Vitro dissolution studies revealed an improved dissolution behaviour for eutectic mixture (69.38 %) as compared to the pure curcumin (40.53%). Conclusion: The study conclude that binary systems improved the dissolution behaviour of poorly water soluble drugs without changing the physiochemical and pharmacological properties of concerned API.

Effect of mechanochemical inclusion of triamterene into sulfobutylether-β-cyclodextrin and its improved dissolution behavior

The formation of inclusion complexes between triamterene (TT) and cyclodextrins (CDs) to increase the water apparent solubility of TT was investigated. UV data showed that the binding constant of the TT/sulfobutylether-β-cyclodextrin (SBE-β-CD) inclusion complex was 510 L/mol. The phenyl ring of TT was inserted into the secondary hydroxy face of SBE-β-CD, as demonstrated by 1H-1H rotating frame nuclear Overhauser effect spectroscopy NMR. Physicochemical properties of solid TT/SBE-β-CD complexes prepared by physical mixing, kneading, freeze-drying, and mechanochemical methods were studied by X-ray diffraction and 13C cross-polarization and magic angle spinning NMR. With the mechanochemical method, the diffraction peak corresponding to TT disappeared, indicating the formation of an inclusion complex. The results of the dissolution test revealed that the solid complex obtained by the mechanochemical method improved the dissolution of TT. The water apparent solubility of TT can be improved by simple mechanical mixing without organic solvents, and improved bioavailability after oral administration is expected.

Preparation and characterization of curcumin solid dispersion using HPMC.

Curcumin solid dispersions were prepared using hydroxypropyl methylcellulose (HPMC) to enhance water solubility of curcumin. The particle size of curcumin solid dispersions was in range from 371 to 528nm and particles were shaped as spherical with wrinkles. The encapsulation efficiency was over 93% for all samples, and water solubility of curcumin was significantly improved to 238µg/mL when the ratio of curcumin to HPMC was 20:80. The results of X-ray diffraction, differential scanning calorimeter, and Fourier transform infrared spectroscopy showed that crystalline form of curcumin changed to amorphous form. Curcumin solid dispersions showed improved dissolution behavior compared to pure curcumin and the curcumin release kinetic studies were applied to find best-fitting model. This study showed a great potential of solid dispersion using HPMC as curcumin delivery system with improved water solubility and oral absorption. PRACTICAL APPLICATION: Curcumin has limited applications in the food industry because of low water solubility. Dongoh water-soluble curcumin (DW-CURs) were prepared by solid dispersion method with HPMC. Our results indicated that curcumin solid dispersions improved the water solubility of curcumin and showed a sustained release, demonstrating its possibility of body application. Therefore, DW-CURs are a promising formulation for application as a functional ingredient in the food industry.

Improved Dissolution Behavior of Dipyridamole Formulation with Precipitation Inhibitor

Background: Physiologically generated supersaturation and subsequent precipitation of a weakly basic drug in the small intestine leads to compromised bioavailability. Methods: In this work, the pH -induced precipitation of dipyridamole (DPD) as a model weakly basic drug in the presence of Eudragit L100 (Eu) and hydroxypropyl cellulose (HPC) was investigated. Inhibitory effects of the polymers on precipitation of DPD at varying drug/polymer ratios were examined. The effects of the polymers on the DPD dissolution property were assessed using drug/polymer physical mixtures (PMs) and solid dispersions (SDs). Results: Significant inhibitory effects on precipitation were found using Eu, while HPC as well inhibited precipitation, but to a lower level than found with Eu. The PMs resulted in higher area under the dissolution curve (AUDC) compared to SDs. For SDs, the AUDC was limited by the slow release of the drug from the polymers in acidic pH which in turn decreased supersaturation of DPD following acidic to neutral pH transition. Conclusion: From these results, it may be supposed that both the ability to create and stabilize supersaturation separately of each other to be important for enhancing dissolution of DPD.

A novel cascade strategy using a nanonized targeted prodrug for enhanced oral delivery efficiency.

It is a great challenge to improve the oral bioavailability for BCS class IV drugs because they have low solubility and poor permeability. However, nanonization and intestinal transporter-targeted prodrugs can increase the solubility and permeability, respectively. Hence, an "increased solubility and improved permeability" cascade strategy was proposed to enhance the dissolution rate and permeability for BCS class IV drugs. In this study, acyclovir glutarate (AG), a prodrug of acyclovir, was synthesized to improve intestinal permeability by targeting monocarboxylate transporter 1 (MCT 1), an intestinal influx transporter. Then, AG was formulated as AG nanoneedles (AGNNs) to improve dissolution behavior. AG was demonstrated to exhibit greatly higher cellular uptake efficiency and permeability than acyclovir due to the MCT 1-mediated active transport. Furthermore, intact AGNNs were also demonstrated to be endocytosed by enterocytes and to be transcytosed potentially. In addition, oral pharmacokinetics showed that the AUC0-24h of AGNNs was 1.89-fold to that of acyclovir. Collectively, these results confirmed that nanonized MCT 1-targeted prodrugs enhanced the oral bioavailability of acyclovir in a cascade manner. Our findings propose a promising strategy to develop BCS class IV drugs and have significant implications for a wide range of such drugs for high oral delivery efficiency.

Eutectics and Salt of Dapsone With Hydroxybenzoic Acids: Binary Phase Diagrams, Characterization and Evaluation

Poor solubility and low dissolution rate of pharmaceuticals in many cases largely limit their bioavailability and efficacy. One of the promising approaches to improve dissolution behavior is to develop new multicomponent solid forms. Herein we use this strategy to synthesize new multicomponent solids of dapsone (DAP), which belongs to BCS class IV, with a series of hydroxybenzoic acid coformers. A new salt of DAP with 2,6-dihydroxybenzoic acid (26DHBA) and 4 eutectics with other hydroxybenzoic acids were reported through comprehensive characterizations using powder X-ray diffraction DSC, and vibrational spectroscopy techniques. The salt formation was evidenced by the presence of ionic interactions detected using FT-IR and Raman spectroscopy, and the stoichiometric ratio was determined to be 1:1. Binary phase diagrams were established to determine the composition of eutectics. The cause for salt and eutectic selection was further understood by computing molecular electrostatic potential (MEP) surface where 26DHBA shows the greatest acidity. Moreover, the powder dissolution study and microenvironment pH measurement reveal that both salt and eutectics of DAP display improvements on the dissolution rate and equilibrium concentration in which the acidity of coformers plays a dominant role. Our findings provide a direction for future coformer screening of multicomponent solids with improved pharmaceutical properties.

Phenytoin-loaded lipid-core nanocapsules improve the technological properties and in vivo performance of fluidised bed granules.

Lipid-core nanocapsules (LNCs) were recently reported by our group as a suitable binder system to produce fluidised bed granules. However, there is still a lack of knowledge about the influence of using these nanocarriers loaded with a drug on the properties of the granules and their in vivo performance. Therefore, this study was designed to produce innovative fluidised bed granules containing phenytoin-loaded LNCs (LNCPHT) as a strategy to evaluate the influence of the presence of the drug-loaded nanocarriers on their in vitro and in vivo properties. Granules were produced using a mixture of maltodextrin and phenytoin (1:0.004 w/w) as substrate. They were prepared by fluid bed granulation using water or LNCPHT as the liquid binder, affording good yields (73-82%) of granules with low moisture content (<5%). Granules prepared with LNCPHT had larger mean size (122μm) compared to maltodextrin primary particles (50μm) due to the formation of solid bridges. Moreover, the use of LNCPHT as the liquid binder improved their powder flow properties. The nanocarriers were recovered after aqueous dispersion (3.00mg.mL-1 of PHT) with a redispersibility close to 90%. After reconstitution in water, granules containing LNCPHT showed an improved dissolution behaviour compared to those prepared without them. In addition, they showed a higher mucoadhesive effect due to a combined effect of the LNCPHT and maltodextrin in the interactions with porcine intestinal mucosa. Regarding the in vivo studies, granules containing the combination of non-encapsulated PHT and PHT-loaded lipid-core nanocapsules increased the latency to seizures compared to placebo granules, showing effective anticonvulsant effect in mice. In conclusion, the use of drug-loaded nanocapsules as binder is an encouraging approach to produce fluidised bed mucoadhesive granules with improved technological properties and in vivo performance.

Design of self-dispersible microsponge containing cyclosporine through wet milling and drop freeze-drying processes to improve dissolution behavior

Cyclosporine (Cyc) is an immunosuppressant used to treat psoriasis and atopic dermatitis and mainly commercialized as a soft capsule due to its poorly water-soluble characteristics. The authors attempted to develop the solid pharmaceutical formulations for oral use (granules, tablet) with improved solubility of Cyc. In this research, a manufacturing method of spherical granules containing nano-sized Cyc particles was newly developed by using the combination between wet milling and drop freeze-drying (DFD) technique. Cyc nanosuspension prepared through wet-milling process was poured dropwise into liquid nitrogen, and the resultant spherical ice grains were freeze-dried to prepare granules with around 300 μm in size. The granules prepared through these sequential processes were identified as porous spherical granules having submicron Cyc particles embedded in water-soluble fiber network structure of additives. When they were placed in aqueous phase, water would immediately penetrate into the matrix of granules through the pores. Subsequently, Cyc particles were spontaneously dispersed into the media as soon as matrix base was dissolved, resulting in the reconstitution of nano-suspension. As a result, the resultant DFD granule, named microsponge, had fast dissolution behavior of more than 80% within 10 min in aqueous phase. The dissolution rate of Cyc from the microsponge strongly depended on the size of embedded Cyc particles, demonstrating that the wet nano-milling must be indispensable process to prepare the microsponge.

Freeze-drying process for the design of porous formulations based on bismuth-potassium-ammonium citrate

The objective of this study was to find optimal freeze-drying process parameters to design porous and friable freeze-dried bismuth-potassium-ammonium citrate (FD BPAC) with improved dissolution behavior. The nucleation and melting temperatures of frozen BPAC solution in water and tert-butanol/water co-solvent system were studied with use of thermal analysis. The phases that resulted on cooling were studied by low-temperature powder x-ray diffraction. BPAC formed an amorphous freeze concentrate on cooling and remained amorphous during freeze-drying and subsequent storage. The nucleation of colloidal bismuth subcitrate (CBS) in the FD BPAC and starting BPAC systems in 0.1 M and 0.01 M HCl was studied by dynamic light scattering (DLS) method. The proposed preparation method of FD BPAC can be the basis for design of formulations with enhanced dissolution rate for bismuth-based triple/quadruple therapy, where FD BPAC simultaneously act as a carrier and an active ingredient.

Design of swellable ordered-mixed spherical drug particles (Swell-OM-spheres) using a dry powder milling and coating technique to improve dissolution behavior

A novel dry powder milling/ordered-mixing technique using a mechanical powder processor was previously developed to improve the dissolution properties of poorly water-soluble drugs. Mecanofused composite particles with an ordered-mixing principle, named OM particles, were designed using corn starch (CS) as a core particle and drug as a coating layer. In the present study this dry powder processing technique was modified to improve the dissolution behavior further by means of two approaches. First, wettable composite particles were produced by co-formulating the water-soluble waxy additive to enhance the hydrophilicity of the outer drug layer. Second, swellable composite particles were designed by replacing CS with a modified starch having expanding property as the core particle. It was found that the latter (swellable) approach was more effective than the former (wettable) one to improve the dissolution behavior of poorly water-soluble model drug. The swellable OM particles promptly expanded on contact with water and induced the effective detachment of fine drug particles from the core particles, resulting in rapid drug release. The present research suggests that the proposed contamination-free dry milling technique, which does not use hard milling balls or beads, can generate spherical drug particles with improved dissolution characteristics.

Evaluation of antioxidant activity of caffeic acid phenethyl ester loaded block copolymer micelles

Caffeic acid phenethyl ester (CAPE), a hydrophobic constituent of poplar propolis of valuable biological activity, was immobilized in poly(ethylene oxide)-b-poly(ε-caprolactone)-b-poly(ethylene oxide) (PEO-b-PCL-b-PEO) copolymer micelles to improve its solubility in water. CAPE was loaded in the micelles by dialysis, achieving ca. 50% encapsulation efficiency. The drug loaded micelles were characterized with a mean diameter of 39 nm, narrow size distribution and slightly positive zeta-potential (approximately 2 mV). The in vitro release profile showed an improved dissolution behavior of micellar CAPE than pure CAPE. In vitro studies on human hepatoma HepG2 and neuronal SH-SY5Y cells demonstrated that the empty PEO-b-PCL-b-PEO micelles were not cytotoxic, whereas the drug loaded micelles exerted cytotoxic effects proportional to CAPE content. The protective activity of pure and micellar CAPE was investigated in a model of H2O2 induced oxidative damage in HepG2 and SH-SY5Y cells. In both cell types, micellar CAPE exhibited better protective activity against the oxidative damage than pure CAPE at very low concentrations (0.1 µg/mL), which is far from the cytotoxic concentration of CAPE-loaded micelles (71 µg/mL). Consequently, the developed micellar formulation has an improved activity against oxidative damage in hepatic and neuronal cells as comparing to pure CAPE.