1225 POSTER A Randomised, Double-blind, Placebo Controlled, Multi-site Study of Subcutaneous Ketamine in the Management of Cancer Pain (original) (raw)
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Formulation and evaluation of docetaxel nanosuspensions: In-vitro evaluation and cytotoxicity
Saudi Pharmaceutical Journal, 2018
The aim of the present study was to formulate the anticancer drug; docetaxel (DOX) as nanoparticles to enhance its biological activity. Methodology: Solvent precipitation method was used to prepare DOX-loaded nanoparticles and was stabilized by different concentrations of hydroxypropyl methylcellulose (HPMC, E5) and sodium deoxycholate (SDC). Results: The results showed that the particle size of the prepared DOX nanoparticles stabilized by SDC was small in comparison to those stabilized by the corresponding HPMC concentrations. The smallest particle size (83.97 nm) was obtained by using SDC as stabilizer at 5% level with zeta potential of À13.6 mV. It was concluded that increasing the stabilizer concentration resulted in increase in both initial and overall cumulative drug release. The release rate in case of nanoparticles stabilized by 5% SDC was 33% and 87% after 1 and 24 h respectively. The results showed that a significant reduction in the viability of FRO cells was observed at all tested time intervals in case of nanoparticles stabilized by 5% SDC at concentrations of 100 and 1000 lM/ml. In contrast, no signs of cytotoxicity was observed for nanoparticles stabilized by 5% HPMC at 10 and 100 lM/ml concentrations.
Drug Development and Industrial Pharmacy, 2015
The aim of this study was to fabricate docetaxel loaded nanocapsules (DTX-NCs) with a high payload using Layer-by-Layer (LbL) technique by successive coating with alternate layers of oppositely charged polyelectrolytes. Developed nanocapsules (NCs) were characterized in terms of morphology, particle size distribution, zeta potential (z-potential), entrapment efficiency and in vitro release. The morphological characteristics of the NCs were assessed using transmission electron microscopy (TEM) that revealed coating of polyelectrolytes around the surface of particles. The developed NCs successfully attained a submicron particle size while the z-potential of optimized NCs alternated between (+) 34.64 ± 1.5 mV to (À) 33.25 ± 2.1 mV with each coating step. The non-hemolytic potential of the NCs indicated the suitability of the developed formulation for intravenous administration. A comparative study indicated that the cytotoxicity of positively charged NCs (F4) was significant higher (p50.05) rather than negative charged NCs (F3), plain drug (DTX) and marketed preparation (Taxotere Õ ) when evaluated in vitro on MCF-7 cells. Furthermore, cell uptake studies evidenced a higher uptake of positive NCs (!1.2 fold) in comparison to negative NCs. In conclusion, formulated NCs are an ideal vehicle for passive targeting of drugs to tumor cells that may result in improved efficacy and reduced toxicity of encapsulated drug moiety.
New Oral Formulation and in Vitro Evaluation of Docetaxel-Loaded Nanomicelles
Molecules, 2016
Intravenous administration of Taxotere ® (a commercial form of docetaxel, DTX) leads to many problems such as hypersensitivity, hemolysis, cutaneous allergy, and patient refusal due to its prolonged injection. The oral absorption of DTX is very low due to its hydrophobic nature. The purpose of this study was to prepare and carry out an in vitro evaluation of DTX-loaded nanomicelles for oral administration in order to increase the oral delivery of DTX. Studied formulations were prepared with the two surfactants Tween 20 and Tween 80 and were characterized for their particle size, zeta potential, stability, encapsulation efficiency, stability studies in gastric fluid and intestinal fluid, toxicity studies in C26 colon carcinoma cell line, and cellular uptake. The prepared nanomicelles with particle size of around 14 nm and encapsulation efficiency of 99% were stable in gastric fluid and intestinal fluid for at least 6 h and IC50 decreased significantly after 72 h exposure compared to that of Taxotere ®. Nanomicelles increased the water solubility of DTX more than 1500 times (10 mg/mL in nanomicelles compared to 6 µg/mL in water). Results of this study reveal that the new formulation of DTX could be used for the oral delivery of DTX and merits further investigation.
Polymeric nanoparticle encapsulating Docetaxel for prolonged and targeted delivery to breast cancer
Chitosan nanoparticles (HA-CHI-NP) containing docetaxel (DTX) were prepared, by ionotropic gelation method and further coupled with hyaluronic acid for targeting effect, in the treatment of breast cancer. Nanoparticles (NP's) have been characterized for the particle size, stability and shape with the help of zeta sizer, zeta potential and SEM. NP's were found to be spherical in shape and the size were around 97.36 ± 3.07 nm with 0.5 polydispersity index. NP's were also characterized for FTIR, DSC and PXRD. The in-vitro drug release of plain DTX and docetaxel loaded chitosan nanoparticle (DTX-CHI-NP) revealed higher and prolonged release of drug from DTX-CHI-NP than with plain DTX. In-vitro cytotoxicity was assessed by MTT assay using MCF-7 cell lines at different concentration (5, 10, 25, 50 and 100 µg/ml) and time intervals (24, 48 and 72h). Higher inhibitory effect of DTX-CHI-NP was observed with an IC50 value of approximately 2.18 µg/ml at 72h. The formulation was also assessed for pharmacokinetic profile, biodistribution and tumour inhibition effect.
Journal of Controlled Release, 2011
Nanoxel-PM™, docetaxel-loaded methoxy-poly(ethylene glycol)-block-poly(D,L-lactide) (mPEG-PDLLA) micellar formulation was prepared in an effort to develop alternative, less toxic and efficacious Tween 80free docetaxel formulation, and its pharmacokinetics, efficacy, and toxicity were evaluated in comparison with Taxotere® in preclinical studies. The mean diameter of the Nanoxel-PM™ was 10-50 nm and the polydispersity of samples exhibited a narrow size distribution and monodisperse unimodal pattern. Pharmacokinetic study in mice, rats and beagle dogs revealed that Nanoxel-PM™ exhibited similar pharmacokinetic profiles (C max , AUC, t 1/2 , CL, V ss) to Taxotere, and the relative mean AUC t and C max of Nanoxel-PM™ to Taxotere® were within 80-120%. Furthermore, excretion study in rats demonstrated that there was no statistically significant difference in the amount excreted in feces or urine as an unmetabolized docetaxel between Nanoxel-PM™ and Taxotere®. Its pharmacokinetic bioequivalence resulted in comparable anti-tumor efficacy to Taxotere® in human lung cancer xenografts H-460 in nude mice as well as in lung, ovary and breast cancer cell lines. Several animal toxicity studies on Nanoxel-PM™ compared with Taxotere® were carried out. In single dose rat and dog model and repeated dose mouse model, both Nanoxel-PM™ and Taxotere® exhibited similar toxic effects on hematology and body weight gain. On the other hand, vehicle related hypersensitivity reactions and fluid retentions were not observed when Nanoxel-PM™ was administered, unlike Taxotere®, in the beagle dog study. Based on these results, it is expected that Nanoxel-PM™ can reduce side effects of hypersensitivity reactions and fluid retention while retaining antitumor efficacy in cancer patients. Currently, Nanoxel-PM™ is under evaluation for bioequivalence with Taxotere® in a multi-center, open-label, randomized, crossover study.
Ankara Üniversitesi Eczacılık Fakültesi dergisi, 2022
Objective: Today, cancer is still among the most common chronic diseases. Nanoparticular drug delivery systems prepared with biocompatible and biodegradable polymers such as polycaprolactone are rational solution for anticancer agents with poor solubility and low bioavailability. The aim of this study is to prepare paclitaxel-loaded polycaprolactone nanoparticles, which is known to be a potent anticancer, and to elucidate in vitro characteristics and release kinetic mechanisms. Material and Method: It was aimed to prepare paclitaxel-loaded polycaprolactone nanoparticles by nanoprecipitation. Preformulation studies were carried out with different molecular weights of polycaprolactone (Mw: 14.000, Mw: 80.000). Nanoparticles were coated with Chitosan or Poly-l-lysine to obtain cationic surface charge and to increase cellular interaction. Comprehensive characterization of formulations and release kinetic studies were performed. Result and Discussion: The particle size of the formulations ranged from 188 nm to 383 nm. Encapsulation efficiency increased to 77% in different formulations. SEM analysis confirmed the nanoparticles were spherical. Within the scope of in vitro release studies, the release continued for up to 96 hours and less than 50% of the therapeutic load was released in the first 24 hours. Mathematical modeling indicated that the
Cancer research, 2011
Docetaxel, an efficient chemotherapeutic drug, exhibits low and variable oral bioavailability due to the active efflux by P-glycoprotein (P-gp) and more so to CYP3A4 gut metabolism. Using a spray-drying technique, docetaxel was incorporated in PLGA [poly(lactic-co-glycolic acid)] nanocapsules (NC) which were embedded in entero-coated microparticles. An oral administration of the NC formulation elicited a higher absolute bioavailability than both a docetaxel solution (276%) and a free docetaxel NC formulation (400%) injected intravenously, a 5-mg/kg dose. The batches (B) I and II NC formulations elicited C max values that were 1,735% and 2,254%, respectively; higher than the C max value of the oral docetaxel solution combined with blank microparticles, a 10-mg/kg dose. No significant difference in AUC (area under curve) was observed between the batches. These unexpected results can be explained only if the pharmacokinetics of docetaxel had been modified. It was shown that NCs released from the microparticles penetrated the enterocytes, bypassing P-gp; apparently circumventing gut metabolism and accumulating within the lymphatic system from where both intact or biodegraded NCs and free docetaxel were progressively released into the circulation as plausibly supported by the fluorescent imaging results. Furthermore, the circulating docetaxel in plasma was unencapsulated and circulated either in free form or bound to albumin. Both free docetaxel NCs and microparticles exhibited in vitro efficacy on WRC 256 cells suggesting that the activity of docetaxel was not altered. This delivery concept has potential for clinical translation, perhaps allowing docetaxel chemotherapy to be switched from intravenous to oral delivery. Cancer Res; 71(8); 1-11. Ó2011 AACR.
Developments in the use of nanocapsules in oncology
Brazilian journal of medical and biological research = Revista brasileira de pesquisas médicas e biológicas / Sociedade Brasileira de Biofísica ... [et al.], 2013
The application of nanotechnology to medicine can provide important benefits, especially in oncology, a fact that has resulted in the emergence of a new field called Nanooncology. Nanoparticles can be engineered to incorporate a wide variety of chemotherapeutic or diagnostic agents. A nanocapsule is a vesicular system that exhibits a typical core-shell structure in which active molecules are confined to a reservoir or within a cavity that is surrounded by a polymer membrane or coating. Delivery systems based on nanocapsules are usually transported to a targeted tumor site and then release their contents upon change in environmental conditions. An effective delivery of the therapeutic agent to the tumor site and to the infiltrating tumor cells is difficult to achieve in many cancer treatments. Therefore, new devices are being developed to facilitate intratumoral distribution, to protect the active agent from premature degradation and to allow its sustained and controlled release. Thi...