Solubility Enhancement of Domperidone by Solvent Change In situ Micronization Technique.

BACKGROUND: Domperidone (DOM), a dopamine receptor antagonist, is used as antiemetic for the treatment of gastroparesis, vomiting, and nausea. The low water solubility of DOM leads to a low dissolution rate and variable bioavailability. The aim of this study was to enhance the solubility of DOM by the preparation of micron-sized particles. MATERIALS AND METHODS: The in situ micronization process was carried out using solvent change method in the presence of Soluplus® or PEG6000 as stabilizing agents. DOM was dissolved in appropriate solvent (acetone and methanol 1:1 v/v), and the stabilizing agent was dissolved in water (as nonsolvent). The nonsolvent was poured rapidly into the drug solution under stirring by a homogenizer, and the resultant was freeze dried. The crystalline shape and particle size of DOM and interaction of DOM with stabilizers were investigated by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and differential scanning calorimetry (DSC), and then, dissolution test was carried out. RESULTS: Optimum formulation was composed of DOM (0.5%) and PEG6000 (0.1%) with the lowest particle size (3 µm) and the highest DE60% (95.95%) as compared to pure DOM (particle size of 13.4 µm and DE60% 52.18%). CONCLUSION: SEM micrographs showed uniform and spherical shape of microcrystals. FTIR, XRD, and DSC studies indicated the micron size of the microcrystals and no interference between the drug and the stabilizer.

Synthesis, in vitro characterization, and anti-tumor effects of novel polystyrene-poly(amide-ether-ester-imide) co-polymeric micelles for delivery of docetaxel in breast cancer in Balb/C mice.

OBJECTIVE: The goal of the present work was to make novel co-polymeric micellar carriers for the delivery of docetaxel (DTX). SIGNIFICANCE: Co-polymeric micelles can not only solubilize DTX and eliminate the need for toxic surfactants to dissolve it, but also cause passive targeting of the drug to the tumor and reduce its toxic side effects. METHODS: Poly(styrene-maleic acid) (SMA) was conjugated to poly (amide-ether-ester-imide)-poly ethylene glycol (PAEEI-PEG). Copolymer synthesis was proven by Fourier transform infrared (FTIR) and 1H-nuclear magnetic resonance (1H-NMR). The SMA-PAEEI-PEG micelles loaded with DTX were prepared and their critical micelle concentration (CMC), zeta potential, particle size, entrapment efficiency, and their release efficiency were studied. MCF-7 and MDA-MB231 breast cancer cells were used to evaluate the cellular uptake and cytotoxicity of the micelles. The antitumor activity of the DTX-loaded nanomicelles was measured in Balb/c mice. RESULTS: The FTIR and HNMR spectroscopy confirmed successful conjugation of SMA and PAEEI-PEG. The drug loading efficiency was in the range of 34.01-72.75% and drug release lasted for 120 h. The CMC value of the micelles was affected by the SMA/PAEEI-PEG ratio and was in the range of 29.85-14.28 µg/ml. The DTX-loaded micelles showed five times more cytotoxicity than the free drug. The DTX loaded micelles were more effective in tumor growth suppression in vivo and the animals showed an enhanced rate of survival. CONCLUSION: The results show that the SMA-PAEEI-PEG micelles of DTX could potentially provide a suitable parenteral formulation with more stability, higher cytotoxicity, and improved antitumor activity.

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.