Poly(glycerol sebacate) nanoparticles for ocular delivery of sunitinib: physicochemical, cytotoxic and allergic studies.

Poly(glycerol sebacate) (PGS) is a new biodegradable polymer with good biocompatibility used in many fields of biomedicine and drug delivery. Sunitinib-loaded PGS/gelatine nanoparticles were prepared by the de-solvation method for retinal delivery and treatment of diabetic retinopathy. The nanoparticles were characterised by Fourier-transform infrared and differential scanning calorimetry. The effects of different formulation variables including drug-to-carrier ratio, gelatine-to-PGS ratio, and glycerine-to-sebacate ratio were assessed on the encapsulation efficiency (EE%), particle size, release efficiency (RE), and zeta potential of the nanoparticles. The in vitro cytotoxicity of PGS/gelatine nanoparticles was studied on L929 cells. Draize test on rabbit eyes was also done to investigate the possible allergic reactions caused by the polymer. Glycerine/sebacic acid was the most effective parameter on the EE and RE. Gelatine-to-PGS ratio had the most considerable effect on the particle size while the RE was more affected by the glycerine/sebacic acid ratio. The optimised formulation (S1G0.7D21.2) exhibited a particle size of 282 nm, 34.6% EE, zeta potential of -8.9 mV, and RE% of about 27.3% for drug over 228 h. The 3-(4,5-dimethylthuazol-2-yl)-2,5-diphenyltetrazolium bromide assay indicated PGS/gelatine nanoparticles were not cytotoxic and sunitinib-loaded nanoparticles were not toxic at concentrations <36 nM.

Effect of freeze drying on stability, thermo-responsive characteristics, and in vivo wound healing of erythropoietin-loaded trimethyl chitosan/glycerophosphate hydrogel.

Erythropoietin (EPO) was successfully incorporated into a bioadhesive thermosensitive hydrogel based on trimethyl chitosan (TMC)/ß-glycerophosphate (GP) for prevention and treatment of oral mucositis in cancerous patients. The aim of the present study was to evaluate the effect of freeze drying on thermo-responsive property of the hydrogel and structural stability of the loaded protein. The freeze-dried EPO-loaded hydrogel were characterized using various methods. Gelation property by rheological analysis, EPO aggregation in formulations by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), protein secondary structure by far ultraviolet-circular dichroism (CD), and the antigenic activity of EPO with ELISA techniques. The healing effects of the freeze-dried formulation was also investigated in Sprague-Dawley rats with chemotherapy-induced mucositis and compared with freshly prepared mixture. Finally, the retention time of the gel in the oral cavity was assessed in healthy volunteers. SDS-PAGE, CD, and ELISA confirmed the stability of conformational structure of loaded and released EPO. Severity of mucositis was markedly reduced in animals treated with freeze-dried EPO hydrogel; whereas the group received normal saline did not show any significant healing. EPO salvia level was decreased rapidly following EPO solution compared to the gel application. Approximately, 40% of EPO was maintained on the buccal areas in patients receiving the hydrogel system after 30 min. Therefore, the TMC/GP could preserve EPO stability after freeze drying and has the potential in the treatment of oral mucositis and other oral or subcutaneous wounds.

Antitumor activity of raloxifene-targeted poly(styrene maleic acid)-poly (amide-ether-ester-imide) co-polymeric nanomicelles loaded with docetaxel in breast cancer-bearing mice.

Purpose Raloxifene (RA) receptors have over-expressed GPER-positive breast cancer tumors. The purpose of this work was to evaluate the antitumor activity and pharmacokinetic behavior of docetaxel (DTX), loaded in RA-targeted nanomicelles, which were designed to overcome a lack of specific distribution and inadequate DTX concentration in tumor tissues, as well as its cytotoxicity and damage to normal tissues. Methods DTX-loaded RA-targeted poly(styrene maleic acid) (SMA)- poly(amide-ether-esterimide)-poly(ethylene glycol) (PAEEI-PEG) nanomicelles were prepared; then, their antitumor activity and survival rate were studied in MC4-L2 tumors induced in BALB/c mice. The pharmacokinetics of DTX-loaded SMA-PAEEI-PEG-RA micelles was also investigated in comparison with free DTX. Results DTX-loaded SMA-PAEEI-PEG-RA micelles inhibited tumor growth considerably and increased animal survival as compared to free DTX and non-targeted micelles. SMA-PAEEIPEG-RA micelles enhanced significantly the area under the curve (AUC0-∞) 1.3 times as compared to free DTX and reduced clearance (CL) from 410.43 ml/kg.h (for free DTX) to 308.8 ml/kg.h (for SMA-PAEEI-PEG-RA micelles). Volume of distribution (Vdss) was also reduced 1.4 times as compared to free DTX. RA-targeted micelles increased tumor inhibition rate (TIR) 1.3 times and median survival time (MST) >1.5 times compared to free DTX. Percentage increase in life span (%ILS) was also enhanced significantly from 41.66% to >83.33% in MC4-L2 tumor-bearing BALB/c mice. Discussion All studies in this work showed the potential of DTX-loaded SMA-PAEEI-PEG-RA micelles in the treatment of GPER-positive receptor breast cancer tumors.

Enhancement of solubility and antidiabetic effects of Repaglinide using spray drying technique in STZ-induced diabetic rats.

The purpose of the study was to enhance the solubility of the poorly water-soluble drug, Repaglinide using spray drying based solid dispersion technique by different carriers including Eudragit E100, hydroxyl propyl cellulose Mw 80 000 and poly vinyl pyrollidone K30. Optimization of the best formulation was carried out according to drug solubility, release profile, particle size and angle of repose of the solid dispersions. The optimized sample was characterized using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). The morphology of the dispersions was studied by SEM. The blood glucose lowering effect of spray dried solid dispersions was studied in normal and streptozocin-induced diabetic rats. The results showed that Eudragit E100 in 1:3 ratio could enhance drug solubility by 100-fold. DSC studies indicated a marked change in melting point of the drug possibly due to strong hydrogen bonds between the drug and Eudragit, while FT-IR study did not show obvious interactions between them. According to XRPD results Repaglinide converted to an amorphous state in the spray dried dispersions. Spray dried Repaglinide reduced the blood glucose level significantly during the 8 h of obtaining blood samples in comparison with untreated drug (p < 0.05).

Physicochemical, Pharmacodynamic and Pharmacokinetic Characterization of Soluplus Stabilized Nanosuspension of Tacrolimus.

BACKGROUND: Tacrolimus, an immunosuppressive drug has a variable pharmacokinetic and poor oral bioavailability due to poor solubility. The aim of the present study was enhancing the solubility and oral bioavailability of this drug. METHODS: Tacrolimus nanoparticles were prepared by precipitation anti-solvent evaporation method. The effect of different parameters including: surfactant type, solvent to nonsolvent ratio and drug to surfactant ratio were studied on the particle size, saturated solubility and dissolution rate of the drug. The solid state characterization was done by fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and scanning electron microscopy. The untreated drug (5 mg.kg-1day-1), nanoparticles or physical mixture of the drug and the stabilizers were administered to rats and blood levels of tacrolimus were assessed by electrochemiluminence method. The oral drug administration was done for 10 days then the changes in white blood cells (WBC) and percent lymphocyte count were determined before drug administration, 5 and 10 days after drug administration. RESULTS: FTIR spectroscopy showed no interaction between the drug and stabilizers. XRPD and DSC studies indicated the amorphous state of the drug in nanosuspensions. The solvent to nonsolvent ratio of 1:20 and drug to surfactant ratio of 1:3 enhanced 185 fold the saturated solubility and 17 fold dissolution rate of the drug. In vivo studies also showed tacrolimus nanoparticles significantly reduced the lymphocyte and WBC, enhanced 66 and 34 fold the AUC0-24 and Cmax of the drug, respectively. CONCLUSION: The precipitation anti-solvent evaporation is a nano-crystalization technique which showed to be an effective approach for enhancing water solubility and bioavailability of tacrolimus.

Enhancement of oral bioavailability of pentoxifylline by solid lipid nanoparticles.

Pentoxifylline (PTX) is a highly water-soluble, hemorheologic drug that undergoes first-pass effect with 20% bioavailability. The solid lipid nanoparticles (SLNs) of PTX were prepared to enhance its oral bioavailability by homogenization, followed by the sonification method. Seven different variables, each at two levels, were studied: lipid type, surfactant type and concentration, speed of homogenizer, acetone:dichloromethane (DCM) ratio, lecithin:lipid ratio, and sonication time. The mean particle size and size distribution, drug entrapment efficiency (EE%), zeta potential, and drug release of the SLNs were investigated. A pharmacokinetic study was conducted in male Wistar rats after oral administration of 10 mg kg(-1) PTX in the form of free drug or SLNs. The z-average particle size, zeta potential, and EE% of the SLNs were at least 250 nm, -30.2 mV, and 70%, respectively. Among the studied factors, the lipid type, surfactant type, and percentage had a significant effect on the particle size. Zeta potential was more affected by lipid type, acetone:DCM ratio, and sonication time. Speed of homogenizer and acetone:DCM ratio had a significant effect on the EE%. The optimized SLN was prepared by 80 mg of cetyl alcohol, 10 mg of lecithin, acetone:DCM ratio (1:2), 30-second sonication, 3% Tween 20, and a mixing rate of 800 rpm. In vitro drug release lasted for about 5 hours. It was found that the relative bioavailability of PTX in SLNs was significantly increased, compared to that of the PTX solution. SLNs offer a promising approach to improve the oral bioavailability of PTX that is affected by a high first-pass effect.