Comparison of adsorption and conjugation of Herceptin on poly(lactic-co-glycolic acid) nanoparticles - Effect on cell internalization in breast cancer cells.

Surfaces of nanoparticles with are commonly modified to enhance the targeting effect. In this study, we performed surface modifications of docetaxel (DTX)-loaded poly(lactic-co-glycolic acid) nanoparticles (PNPs) with Herceptin® (HCT) to improve the internalization and cytotoxicity in breast cancer cells. The PNPs were prepared with surfactant, poly(ethylene-alt-maleic anhydride) (PEMA), including a number of carboxyl groups for conjugation. Three types of PNPs were prepared via different methods such as adsorption, charged adsorption, and bio-conjugation. The PNPs were evaluated in terms of physical properties, stability, cellular uptake and cytotoxicity. The docetaxel-loaded PNPs with HCT were successfully surface-modified with mean particle sizes of 338.4 ±â€¯59.8 nm (DTX-PNPs), 353.9 ±â€¯67.5 nm (HCT-A-DTX-PNPs), 544.8 ±â€¯301.7 nm (HCT-C-DTX-PNPs), and 499.1 ±â€¯71.9 nm (HCT-B-DTX-PNPs). Cellular uptake of HCT-B-PNPs was 5.0-, 4.4-, and 4.6-fold higher than that of PNPs in BT-474, SK-BR-3, and MCF-7 cells, respectively, at 2 h. At 40 µg/mL, HCT-B-DTX-PNPs showed a higher cytotoxicity toward BT-474, SK-BR-3, and MCF-7 cells than the other formulations. In conclusion, HCT-B-DTX-PNPs were found to possess a higher affinity for breast cancer cells and induce a stronger cytotoxicity than that of other PNPs.

Solid dispersion of dutasteride using the solvent evaporation method: Approaches to improve dissolution rate and oral bioavailability in rats.

The aim of this study was to develop a dutasteride (DUT) solid dispersion (SD) using hydrophilic substances to enhance its dissolution (%) and oral bioavailability in rats. DUT-SD formulations were prepared with various co-polymers using a solvent evaporation method. The physical properties of DUT-SD formulations were confirmed using field emission scanning electron microscopy (FE-SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and attenuated total reflectance Fourier transform infrared (ATR-FT-IR) spectroscopy. The toxicity and oral bioavailability of DUT-SD formulations were evaluated. Tocopheryl polyethylene glycol-1000-succinate (TPGS) was chosen as the solubilizer; and methylene chloride, and Aerosil® 200 or microcrystalline cellulose (MCC) were chosen as the solvent and carrier, respectively, based on a solubility test and pre-dissolution study. The dissolution levels of DUT-SD formulations were 86.3 ±â€¯2.3% (F15) and 95.1 ±â€¯1.9% (F16) after 1 h, which were higher than those of the commercial product, i.e., Avodart® (75.8 ±â€¯1.5%) in 0.1 N HCl containing 1% (w/v) sodium lauryl sulfate (SLS). The F16 formulation was found to be stable, after assessing its dissolution (%) and drug content (%) for 6 months. The DUT-SD formulations resulted in relative bioavailability (BA) values of 126.4% (F15) and 132.1% (F16), which were enhanced compared to that of Avodart®. Dissolution (%) and relative BA values were both increased by hydrogen interaction between TPGS and DUT. This study might contribute to a new formulation (powder) whose oral bioavailability is greater than that of Avodart® (soft capsule), which could facilitate to the use of the SD system during the production process.

Tadalafil solid dispersion formulations based on PVP/VA S-630: Improving oral bioavailability in rats.

Here, solid dispersion (SD) techniques were utilized to improve the oral bioavailability of tadalafil (TDF). Poly(vinyl pyrrolidone-covinyl acetate) (PVP/VA S-630; 60% VP and 40% VA; MW 50,000) SD formulations were previously found to improve the solubility and dissolution (%) of TDF. The effect of various weak acids and bases on SD formulations was also investigated herein. PVP/VA S-630 SD formulations in combination with weak acids and bases increased the apparent solubility of TDF. After 1h, the apparent solubility of PVP/VA S-630 SD formulations with MgO, meglumine, and tartaric acid were significantly higher by 387.0±4.17, 376.8±9.88, and 308.8±4.17µg/mL, respectively, than those of SD formulations without weak acids and bases (166.8±0.50µg/mL). The dissolution (%) of SD formulations with weak acids was under 60%; however, the dissolution (%) of those containing MgO, meglumine, and NaHCO3 was over 80% in distilled water (specifically 85.6%, 89.9%, and 91.6%, respectively). The optimal SD formulation contained meglumine (B-2); both its apparent solubility after 24h and dissolution (%) were the highest among all SD formulations. The B-2 SD formulation showed no toxicity in Caco-2 cells after 24h. The area under the concentration-time curve (AUClast) and peak plasma concentration (Cmax) of the orally administered B-2 SD formulation was greater than that with Cialis® powder in rats. We conclude that the B-2 SD formulation significantly improves the apparent solubility and dissolution (%) of TDF over that of commercially available products (i.e., Cialis®). Moreover, the B-2 SD formulation improves the relative bioavailability (BA) of TDF (21.9%) over that of Cialis®.

Use of acidifier and solubilizer in tadalafil solid dispersion to enhance the in vitro dissolution and oral bioavailability in rats.

The purpose of this study is to improve the solubility, in vitro dissolution, and oral bioavailability in rats of tadalafil (TDF) by using SD technique with a weak acid and a copolymer. TDF-SD was prepared via solvent evaporation, coupled with the incorporation of an acidifier and solubilizer. Tartaric acid enhanced the solubility of TDF over 5-fold in DW, and Soluplus® enhanced the solubility of TDF over 8.7-fold and 19.2-fold compared to that of TDF (pure) in DW and pH 1.2 for 1h, respectively. The optimal formulation of TDF-SD3 was composed of TDF vs Tartaric acid vs Soluplus® vs Aerosil=1:1:3:3. The in vitro dissolution rate of TDF-SD3 in DW, pH 1.2 and pH 6.8 buffer (51.5%, 53.3%, and 33.2%, respectively) was significantly higher than that of the commercial product (Cialis®) powder (16.5%, 15.2%, and 14.8%, respectively). TDF was completely transformed to an amorphous form as shown in SEM, DSC and PXRD data. The stability of TDF-SD3 included drug contents and in vitro dissolution for 1 month were similar to those of Cialis®, and the amorphous form of TDF-SD3 was well maintained for 6 months. The TDF-SD3 formulation improved the relative bioavailability (BA) and peak plasma concentration (Cmax) compared to that of Cialis® powder after oral administration in rats as 117.3% and 135.7%, respectively. From the results, we found that the acidifier increased the wettability of TDF, and the solubilizer improved solubility through hydrogen bonding with TDF, thereby increasing the solubility, dissolution and oral bioavailability of TDF in TDF-SD3.

Enhancing the in vitro anticancer activity of albendazole incorporated into chitosan-coated PLGA nanoparticles.

To improve the solubility and anticancer activity of albendazole (ABZ), chitosan (CS)-coated poly-dl-lactic-co-glycolic acid (PLGA) nanoparticles were developed. CS was used to coat ABZ-loaded PLGA nanoparticles to enhance both mucoadhesiveness and colloidal stability. CS-coated PLGA nanoparticles were prepared by suspending the nanoparticles in CS solution after solvent diffusion. The CS-coated PLGA nanoparticles were characterized, and ABZ release was studied in vitro from various formulations. The mucoadhesive properties and in vitro anticancer activities of CS-coated PLGA nanoparticles were investigated by measurement of zeta potentials and the MTT assay, respectively. Spherical nanoparticles below 500nm in diameter were successfully prepared; the particle size distribution was narrow. Complete encapsulation of ABZ in CS-coated PLGA nanoparticles was confirmed by SEM, FTIR, DSC, and XRD. The particle sizes of CS-coated PLGA nanoparticles were in the range of 260-480nm; the encapsulation efficiency was 43.4-54.6%; and the yield 58.5-67.8%. The zeta potential of CS-coated nanoparticles was above +27mV and stability was maintained for 4 weeks. At pH 7.4, the in vitro release of ABZ from nanoparticles (P188-5) was 200-fold higher than that from untreated ABZ; this persisted for 12h. Moreover, ABZ release from CS-coated PLGA nanoparticles (P188-CS0.5) was 1.5-fold higher than that from untreated ABZ at pH 1.2. Additionally, the ABZ-loaded CS-coated nanoparticles exhibited superior mucoadhesion and improved cytotoxicity. The results show that CS coating of PLGA nanoparticles may improve the anticancer effect and the mucoadhesive properties of ABZ-loaded nanoparticles.

Solubilization and formulation of chrysosplenol C in solid dispersion with hydrophilic carriers.

We investigated how to overcome problems associated with the solubility, dissolution, and oral bioavailability of the poorly water-soluble drug compound, chrysosplenol C (CRSP), as well as the effects of single and binary hydrophilic polymers (PVP K-25 and/or PEG 6000) on the solubility and dissolution parameters of CRSP. Then an optimized formulation was further developed with a surfactant. To select a surfactant suitable for a CRSP-loaded solid dispersion (SD), the solubility of CRSP in distilled water containing 1% surfactant was compared with the solubilities in other surfactants. Sodium lauryl sulfate (SLS) showed the highest drug solubility. Overall, a formulation containing CRSP, binary hydrophilic polymers (PVP and PEG 6000), and SLS at a ratio of 2.0/0.2/1.1/0.7 showed the optimum in vitro release profile. This optimized formulation had better safety properties than pure CRSP in cell viability examinations. SD formulations were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), and Fourier-transform infrared (FT-IR) spectroscopy. Our optimized SD formulation is expected to improve the bioavailability of CRPS because it improves the solubility and dissolution rate of CRSP.