MONTELUKAST SPRAY DRIED MICROPARTICLES: PREPARATION, EXCIPIENTS SELECTION AND IN VITRO PULMONARY DEPOSITION

Objective: This study focused on the preparation of montelukast sodium (MTK) fast release pulmonary targeted microparticles using the spray drying technique.Methods: The effect of addition of different excipients namely: mannitol, leucine and ovalbumin on the physico-chemical characteristics of MTK spray dried powders were investigated. Powder flow properties, drug association efficiency as well as microparticle size and mass median aerodynamic diameter were determined. The prepared microparticles were characterized using FT-IR and TGA. The powder crystallographic and thermal properties were studied using DSC and X-ray powder diffraction. A twin stage impinger was used to evaluate in vitro pulmonary deposition from which the inhalation indices were derived.Results: The tested excipients showed no adverse chemical interactions with the drug based on FT-IR. The best inhalation indices were obtained with powders spray dried with leucine followed by leucine/mannitol mixtures with MMAD of 1.73±0.08 and 1.36±0.16 and fine particle fraction of 60.55±1.63 and 52.31±3.52, respectively. The dried powders showed good physico-chemical stability for up to 6 mo storage.Conclusion: The developed MTK spray dried particles may offer a good platform for the targeted pulmonary delivery of MTK overcoming the major biological barriers

Development and validation of a simple and rapid UPLC method for the in-vitro estimation of (-)-epigallocatechin-3-gallate in lipid-based formulations

(-)-Epigallocatechin gallate (EGCG) is a catechin found in green tea that has potential health benefits, such as anti-oxidant, anti-carcinogenic and anti-inflammatory effects. A rapid and sensitive Ultra-Performance Liquid Chromatographic (UPLC) method was developed and validated for the estimation of (-)-epigallocatechin-3-gallate in lipid-based formulation. The UPLC method was conducted on C18 analytical column (50 mm × 2.1 mm, 1.8 μm particle size). The mobile phase consisted of a mixture of acetic acid (1%, v:v; pH = 3), acetonitrile and water at volume ratio of 13:15:72 delivered at a flow rate of 0.5 mL/min. The diode array detector (DAD) acquisition wavelength was set at wavelengths 210 and 280 nm. Caffeine was used as internal standard. The tested validation parameters, i.e., selectivity, linearity, accuracy, precision, and sensitivity (Limit of detection and limit of quantification) were determined at both wavelengths. Results revealed that caffeine and EGCG peaks were eluted at retention times of 0.55 and 0.85 minutes, respectively. The calibration curve was linear over the concentration range of 10-60 μg/mL, with coefficients of determination (r2) of 0.9993 and 0.9998 nm at 210 and 280 nm, respectively. All the validation parameters were found within the acceptable range. The proposed method was successfully applied for the quantitation of EGCG in lipid-based formulation and statistical analysis with a reported method showed no significant difference at p < 0.05. Therefore, the proposed analytical method for EGCG can be considered as a rapid, selective and accurate analytical method that can be used for the quantitative analysis of EGCG

Nanostructured lipid carriers loaded with simvastatin: effect of PEG/glycerides on characterization, stability, cellular uptake efficiency and <i>in vitro</i> cytotoxicity

<p><b>Objective:</b> The aim of this study is to evaluate the use of PEG/glycerides of different HLB; oleoyl macrogol-6-glycerides (Labrafil^® M 1944 CS) and caprylocaproylmacrogol-8-glycerides (Labrasol^®), compared to Labrafac lipophile^® as PEG-free glyceride in the preparation of nanostructured lipid carriers (NLCs). PEG/glycerides are suggested to perform a dual function; as the oily component, and as the PEG-containing substrate required for producing the PEGylated carriers without physical or chemical synthesis.</p> <p><b>Methods:</b> Lipid nanocarriers were loaded with simvastatin (SV) as a promising anticancer drug. An optimization study of NLC fabrication variables was first conducted. The effect of lyophilization was investigated using cryoprotectants of various types and concentrations. The prepared NLCs were characterized in terms of particle size (PS), size distribution (PDI), zeta potential (ZP), drug entrapment, <i>in vitro</i> drug release, morphology and drug–excipient interactions. The influence of glycerides ± PEG on the cytotoxicity of SV was evaluated on MCF-7 breast cancer cells, in addition to the cellular uptake of fluorescent blank NLCs.</p> <p><b>Results:</b> The alteration between different oil types had a significant impact on PS, ZP and drug release. Both sucrose and trehalose showed the lowest increase in PS and PDI of the reconstituted lyophilized NLCs. The <i>in vitro</i> cytotoxicity and cellular uptake studies indicated that SV showed the highest antitumor effect on MCF-7 cancer cells when loaded into Labrasol^® NLCs demonstrating a high cellular uptake as well.</p> <p><b>Conclusion:</b> The study confirms the applicability of PEG/glycerides in the development of NLCs. Encapsulating SV in Labrasol^®-containing NLC could enhance the antitumor effect of the drug.</p

Passive targeting and lung tolerability of enoxaparin microspheres for a sustained antithrombotic activity in rats

<p>Pulmonary bed can retain microparticles (MP) larger than their capillaries’ diameter, hence we offer a promising way for lung passive targeting following intravenous (IV) administration. In this study, enoxaparin (Enox)-albumin microspheres (Enox-Alb MS) were, optimally, developed as lung targeted sustained release MP for IV use. Lung tolerability and targeting efficiency of Enox-Alb MS were tested, and the pharmacokinetic profile following IV administration to albino rats was constructed. <i>In vivo</i> studies confirmed high lung targeting efficiency of Enox-Alb MS with lack of potential tissue toxicity. The anticoagulant activity of the selected Alb MS was significantly sustained for up to 38 h compared to 5 h for the market product. Alb MS are promising delivery carriers for controlled and targeted delivery of Enox to the lungs for prophylaxis and treatment of pulmonary embolism.</p

Tunable Biodegradable Nanocomposite Hydrogel for Improved Cisplatin Efficacy on HCT-116 Colorectal Cancer Cells and Decreased Toxicity in Rats

This work describes the development of a modified nanocomposite thermosensitive hydrogel for controlled cisplatin release and improved cytotoxicity with decreased side effects. The system was characterized in terms of physical properties, morphological architecture and in vitro cisplatin release. Cytotoxicity was tested against human colorectal carcinoma HCT-116. In vivo studies were conducted to evaluate the acute toxicity in terms of rats’ survival rate and body weight loss. Nephro and hepatotoxicities were evaluated followed by histopathological alterations of various tissue organs. Nanocomposite thermosensitive hydrogel containing nanosized carrier conferred density and stiffness allowing a zero order drug release for 14 days. Enhanced cytotoxicity with 2-fold decrease in cisplatin IC₅₀ was accomplished. A linear in vivo–in vitro correlation was proved for the system degradation. Higher animal survival rate and lower tissue toxicities proved the decreased toxicity of cisplatin nanocomposite compared to its solution

Polyethylene Glycol Conjugated Polymeric Nanocapsules for Targeted Delivery of Quercetin to Folate-Expressing Cancer Cells In Vitro and In Vivo

In this work we describe the formulation and characterization of chemically modified polymeric nanocapsules incorporating the anticancer drug, quercetin, for the passive and active targeting to tumors. Folic acid was conjugated to poly (lactide-co-glycolide) (PLGA) polymer to facilitate active targeting to cancer cells. Two different methods for the conjugation of PLGA to folic acid were employed utilising polyethylene glycol (PEG) as a spacer. Characterisation of the conjugates was performed using FTIR and 1H-NMR studies. The PEG and Folic acid content was independent on the conjugation methodology employed. PEGylation has shown to reduce the size of the nanocapsule, moreover, Zeta potential was shown to be polymer-type dependent. Comparative studies on the cytotoxicity and cellular uptake of the different formulations by HeLa cells, in the presence and absence of excess folic acid, were carried out using MTT assay and Confocal Laser Scanning Microscopy, respectively. Both results confirmed the selective uptake and cytotoxicity of the folic acid targeted nanocapsules to the folate enriched cancer cells in a folate-dependent manner. Finally the passive tumor accumulation and the active targeting of the nanocapsules to folate-expressing cells were confirmed upon intravenous administration in HeLa or IGROV-1 tumor-bearing mice. The developed nanocapsules provide a system for targeted delivery of a range of hydrophobic anti-cancer drugs in vivo