Dissolution enhancement of gliclazide using pH change approach in presence of twelve stabilizers with various physico-chemical properties

Purpose. The micronization using milling process to enhance dissolution rate is extremely inefficient due to a high energy input, and disruptions in the crystal lattice which can cause physical or chemical instability. Therefore, the aim of the present study is to use in situ micronization process through pH change method to produce micron-size gliclazide particles for fast dissolution hence better bioavailability. Methods. Gliclazide was recrystallized in presence of 12 different stabilizers and the effects of each stabilizer on micromeritic behaviors, morphology of microcrystals, dissolution rate and solid state of recrystallized drug particles were investigated. Results. The results showed that recrystallized samples showed faster dissolution rate than untreated gliclazide particles and the fastest dissolution rate was observed for the samples recrystallized in presence of PEG 1500. Some of the recrystallized drug samples in presence of stabilizers dissolved 100% within the first 5 min showing at least 10 times greater dissolution rate than the dissolution rate of untreated gliclazide powders. Micromeritic studies showed that in situ micronization technique via pH change method is able to produce smaller particle size with a high surface area. The results also showed that the type of stabilizer had significant impact on morphology of recrystallized drug particles. The untreated gliclazide is rod or rectangular shape, whereas the crystals produced in presence of stabilizers, depending on the type of stabilizer, were very fine particles with irregular, cubic, rectangular, granular and spherical/modular shape. The results showed that crystallization of gliclazide in presence of stabilizers reduced the crystallinity of the samples as confirmed by XRPD and DSC results. Conclusion. In situ micronization of gliclazide through pH change method can successfully be used to produce micron-sized drug particles to enhance dissolution rate

Optimizacija svojstava samoorganiziranja graft kopolimera metoksi poli(etilen glikola) i masnih kiselina pri pripravi nanonosača s uklopljenim etopozidom

The objective of this work was to study the effect of fatty acid chain length grafted to methoxy poly(ethylene glycol) (mPEG) on self assembling properties of micelles for etoposide delivery. Three amphiphilic copolymers were synthesized using mPEG, myristic acid, stearic acid and behenic acid through an esteric linkage. The particle size and zeta potential of the micelles were determined by the dynamic light scattering method. Etoposide was loaded into micelles by film casting using various drug/polymer ratios. Drug release was studied by the dialysis method. The structure of copolymers was confirmed by 1H NMR and FTIR. Critical micellar concentration (CMC) measurements showed that the longer hydrophobic chains formed more thermodynamically stable micelles. Among the prepared copolymers, etoposide showed the highest solubility in the mPEG-behenic copolymer. Drug loading efficiency depended on the hydrophobic chain length and drug/polymer ratio. The highest drug loading efficiency was found in mPEG-myristic micelles with 1:20 drug/polymer ratio. Micelles released 80 % of loaded drug within about 5 h.Cilj je rada bio ispitati svojstva samoorganiziranja micela pripravljenih od graft kopolimera metoksipolietilenglikola (mPEG) i masnih kiselina različite duljine lanca za uklapanje etopozida. Sintetizirana su tri amfifilna kopolimera povezivanjem miristinske, stearinske i behenične kiseline esterskom vezom s mPEG. Veličina i zeta-potencijal micela određeni su metodom dinamičkog raspršivanja svjetlosti. Micele s uklopljenim etopozidom pripravljene su film-metodom pri različitim omjerima lijeka i kopolimera. Oslobađanje lijeka iz micela ispitano je metodom dijalize. Struktura kopolimera potvrđena je 1H NMR i FTIR spektroskopijom. Određivanjem kritičnih micelizacijskih koncentracija utvrđeno je da se s povećanjem duljine hidrofobnog lanca na kopolimerima stvaraju termodinamički stabilnije micele. Među sintetiziranim kopolimerima, micele građene od kopolimera mPEG i behenične kiseline imaju najbolji solubilizacijski kapacitet za etopozid. Učinkovitost uklapanja lijeka u micele ovisi o duljini hidrofobnog dijela u kopolimeru i omjeru lijeka i kopolimera. Najveća učinkovitost uklapanja lijeka utvrđena je za micele mPEG i miristinske kiseline pri omjeru lijeka i kopolimera 1:20. Oko 80% uklopljenog lijeka oslobađa se iz micela tijekom 5 sati

Chitosan-titanium dioxide-glucantime nanoassemblies effects on promastigote and amastigote of Leishmania major

The purpose of the present study was to design nanoassemblies of chitosan-titanium dioxide (TiO2) nanoparticles (NPs) loaded with glucantime for using their synergistic effects and enhancing the toxic effects of glucantime on Leishmania parasites. The nanoassemblies were prepared by electrostatic interactions and optimized by a response surface central composite design. The effects of glucantime, chitosan and TiO2 NPs amounts were studied on the particle size, zeta potential, loading efficiency, and release efficiency of drug from nanoassemblies. The conjugation of TiO2/chitosan-glucantime was verified by UV spectroscopy and changes in surface charge of NPs. The anti-promastigots effect of glucantime loaded in TiO2/chitosan nanoassemblies was studied by tripan blue dye test and their anti-amastigotes effect by counting the average number of parasites per infected J774 macrophages in 100 cells. The optimized formulation obtained by using 12.5 mg glucantime, 25 mg chitosan and 6 mg TiO2 NPs. Although TiO2 NPs alone were effective more than negative control in reduction of promastigots and amastigotes but they didn't show significant difference compared with free glucantime (p > 0.05). However, at the concentration of 50 μg/mL and after 72 h exposure nanoassemblies decreased the proliferation of L. major promastigotes and amastigotes 13 and 4-fold, respectively compared with glucantime alone. © 2017 Elsevier B.V

Comparison of cytotoxic effect of β-cyclodextrin and dextran micelles loaded with doxorubicin in KG-1 cells

زمینه و هدف: آنتراسیکلین ها درمان اصلی لوسمی حاد میلوژنز می باشند، اما استفاده از آن ها به دلیل عوارض جاننی محدود شده است. استفاده از میسل های پلیمری برای دارورسانی هدفمند دوکسوروبیسین توسط گیرنده های فولات برای لوسمی حاد میلوژنز می تواند این عوارض را کاهش دهد. این مطالعه با هدف مقایسه سمیت سلولی میسل های تهیه شده از بتاسیکلودکسترین و دکستران حاوی دوکسوروبیسین بر رده ی سلولی KG-1 انجام شده است. روش بررسی: در این مطالعه تجربی آزمایشگاهی، کونژوگه های رتینوئیک اسید/ سیکلودکسترین/ فولیک اسید و رتینوئیک اسید/ دکستران/ فولیک اسید به روش استریفیکاسیون تهیه شدند. بارگیری دارو در میسل ها به روش انحلال مستقیم انجام شد. نانوذرات میسلی بهینه سازی شده براساس اندازه ذره ای، پتانسیل زتا، اندکس پلی دیسپرسیتی، کارایی بارگیری و کارآیی رهش دوکسوروبیسین انتخاب شدند. جهت مطالعه اثر ممانعت از رشد سلولی بر رده سلولی KG-1 از روش رنگ سنجی MTT استفاده شد. یافته ها: دوکسوروبیسین بارگیری شده در نانو ذرات بهینه تهیه شده از کونژوگه ی رتینوئیک اسید/ سیکلودکسترین/ فولیک اسید در غلظت g/mlµ377/0، دارای اثر ممانعت از رشد سلولی حدود 5/10 برابر دوکسوروبیسین آزاد، 3 برابر دوکسوروبیسین بارگیری شده در میسل های رتینوئیک اسید/ سیکلودکسترین و 3/8 برابر دوکسوروبیسین بارگیری شده در میسل های رتینوئیک اسید/ دکستران/ فولیک اسید بود (05/0>P). دوکسوروبیسین بارگیری شده در نانو ذرات بهینه تهیه شده از کونژوگه رتینوئیک اسید/ دکستران/ فولیک اسید در غلظت g/mlµ377/0، دارای اثر ممانعت از رشد سلولی حدود 3/1 برابر دوکسوروبیسین آزاد و 2/1 برابر دوکسوروبیسین بارگیری شده در میسل های رتینوئیک اسید/ دکستران بود (05/0>P). نتیجه گیری: نانو ذرات تهیه شده از سیکلودکسترین حاوی دوکسوروبیسین اثربخشی بیشتری علیه سلول های سرطانی KG-1 نسبت به نانو ذرات تهیه شده از دکستران حاوی دوکسوروبیسین و داروی آزاد دارد

Chitosan-Cellulose Composite for Wound Dressing Material. Part 2. Antimicrobial Activity, Blood Absorption Ability, and Biocompatibility

Chitosan (CS), a polysaccharide derived from chitin, the second most abundant polysaccharide, is widely used in the medical world because of its natural and nontoxic properties and its innate ability for antibacterial and hemostasis effects. In this study, the novel composites containing CS and cellulose (CEL) (i.e., [CEL + CS]), which we have previously synthesized using a green and totally recyclable method, were investigated for their antimicrobial activity, absorption of anticoagulated whole blood, anti-inflammatory activity through the reduction of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and the biocompatibility with human fibroblasts. The [CEL + CS] composites were found to inhibit the growth of both Gram positive and negative micro-organisms. For examples, the regenerated 100% lyophilized chitosan material was found to reduce growth of Escherichia coli (ATCC 8739 and vancomycin resistant Enterococcus faecalis (ATCC 51299) by 78, 36, and 64%, respectively. The composites are nontoxic to fibroblasts; that is, fibroblasts, which are critical to the formation of connective tissue matrix were found to grow and proliferate in the presence of the composites. They effectively absorb blood, and at the same rate and volume as commercially available wound dressings. The composites, in both air-dried and lyophilized forms, significantly inhibit the production of TNF-α and IL-6 by stimulated macrophages. These results clearly indicate that the biodegradable, biocompatible and nontoxic [CEL + CS] composites, particularly those dried by lyophilizing, can be effectively used as a material in wound dressings

Co-delivery of Curcumin and Imatinib by Nanostructured Lipid Carriers in the Treatment of Lymphoma

The purpose of this study was to encapsulate curcumin and imatinib in nanostructures and target them with HDL for scavenger receptor type B-1, a high-affinity HDL receptor expressed by lymphoma cells. Introduction: Among numerous drug-delivery approaches, high-density lipoprotein (HDL) nanocarriers have proven particularly applicable for delivering highly hydrophobic drugs by their high affinity to SR-B1. In this study, we have investigated the enhancement of the therapeutic impact of curcumin, a naturally occurring polyphenol substance extracted from the roots of Curcuma Longa that has been extensively studied for its broad-spectrum anticancer effects by co-delivery with imatinib. The potential benefits of curcumin are, however, limited due to its poor water solubility and rapid degradation which results in low bioavailability on administration. The drug of choice in lymphoma is imatinib. Methods and Results: Curcumin and imatinib nanostructured lipid carriers (NLCs) were prepared by dissolving 10 mg of lecithin, 2 mg of stearyl amine, 25% of oleic acid and 7.5 mg of curcumin or 2.5 mg of imatinib in 2 ml of ethanol (mixed with 100 µl acetone or 100 µl chloroform) and then added to 20 ml of stirring deionized water including 0.5 % of Tween 80 at room temperature and was left for 3 hours for solvent evaporation. The NLCs were conjugated to HDL by EDC chemistry and then tested by MTT assay for their cytotoxicity on two types of lymphoma cells including; Ramus as B cell lymphoma expressing SR-B1 receptors and Jurkat as T cell lymphoma without SR-B1 receptors. The results showed the best designed nanoparticles had the particle size of 182 nm, zeta potential of -3 mV, curcumin and imatinib loading efficiency of 100 % and 98 %, respectively. They released imatinib and curcumin within 24 and 48 hours, respectively. The NLCs caused more significant cytotoxicity than each separate drug encapsulated in NLCs or free drugs. Conclusions: Co-delivery of curcumin and imatinib in NLCs targeted by HDL may be more useful than imatinib alone in the treatment of B cell lymphoma

Model-Based Testing for System-Level Safety of Autonomous Underwater Robots

For the deployment of autonomous robotic systems in mission- and safety-critical underwater environments, aspects such as reasoning and planning need to be designed to operate in highly dynamic, uncertain environments while assuring a safe and reliable operation. However, systems are often designed or developed with safety analysis as a separate engineering process. In this paper, to tackle these challenges, we propose an initial research vision and plan with the envisioned contributions towards designing an approach for system-wide modeling and Model-Based Testing to support safety assessments of autonomous underwater robots

Enhancement of Drug Solubility: Review Abstract Articles

Introduction: Poor water-solubility is a common characteristic of drug candidates in pharmaceutical development pipelines today. Various  processes  have  been  developed  to  increase  the  solubility,  dissolution  rate  and bioavailability  of  these  active  ingredients  belonging  to  BCS  II  and  IV  classifications. Therefore, enhancement in the solubility of such drugs would be important to the pharmaceutical industry. There is a number of formulation approaches to resolve the problems of low solubility and low bioavailability of drugs. These techniques for solubility enhancement have some limitations and hence have limited utility in solubility enhancement. Nanotechnology can be used to resolve  the  problems  associated  with  these  conventional approaches  for  solubility  and  bioavailability  enhancement Methods and Results: There are many techniques which are used to enhance the aqueous solubility. The ability to increase aqueous solubility can thus be a valuable aid to increase efficiency and/or reducing side effects of drugs. This is true for parenterally, topically and orally administered solutions. Hence various techniques are used for the improvement of the solubility of poorly water soluble drugs including hydrotrophy, use of salt form, use of precipitation inhibitors, alteration of pH of the drug micro-environment, solvent deposition, precipitation pH adjustment, co-solvency, micellar solubilization, super critical fluid techniques, solid dispersions, complexation, micro-emulsions, solid solutions, eutectic mixtures, selective adsorption on insoluble carriers, evaporative precipitation into aqueous solutions, use of surfactants, use of amorphous, anhydrates, solvates and nanonisation. Conclusions: Solubility is a major challenge for formulation scientist. Any drug to be absorbed must be present in the form of solution at the site of absorption. Various techniques used for the enhancement of the solubility of poorly soluble drugs like physical and chemical modification of have specific advantages and draw backs. Selection of solubility improving method depends on drug property, site of absorption, and required dosage form characteristics

A Double-Blind Randomized Controlled Trial on the Effectiveness of Acceptance and Commitment Therapy on Resiliency, Anxiety and Perceived Stress in Women with Breast Cancer

Introduction: Growing evidence shows that mindfulness based on self-help interventions have advantages for physical and psychological health in different populations. The mindfulness based emotional balance is a new program and efficacy of which has not been investigated in self-help format.  Methods: This study was a randomized control trial (RCT) with wait-list control. After screening and applying inclusion and exclusion criteria eighty students of Kermanshah University of medical sciences were assigned randomly to the mindfulness-based emotional balance self-help or the wait list control group. Anxiety, depression, stress, and mindfulness were measured prior to the intervention after the intervention, and two-month after end of intervention as follow-up. DASS-21 and MAAS were used.  Results: Significant decrease in anxiety, depression, and stress in addition to a significant increase in mindfulness in the experimental group in the posttest. However, there were no significant changes in any of the aforesaid measures in the wait list control group. The resultant benefits were persistent in the two-month follow-up. Conclusion: Based on the results of this study, this type of treatment can be used as an efficient and cost-effective method to improve psychological problems such as stress, depression and anxiety.  Declaration of Interest: Non

Mucoadhesive microspheres of chitosan and polyvinyl alcohol as a carrier for intranasal delivery of insulin: in vitro and in vivo studies

The aim of this study was to investigate the capabilities of chitosan microspheres as drug carrier system in co-formulation with polyvinyl alcohol (PVA), to improve the systemic absorption of intranasal insulin delivery. Insulin loaded microspheres was developed from varying ratio of chitosan solutions along with polyvinyl alcohol (PVA) as additive polymer using spray drying method. Different formulations were developed and morphological studies of the optimized formulas showed that the size range of spherical shaped particulate matters existed from 200 nm to 2 mm. It was clearly observed that physicochemical properties of the microspheres were extensively affected by changing the concentration ratio of the two polymeric materials. In vitro studies of insulin release pattern was performed in various time intervals up to 24 h. It was evident that microspheres made up of chitosan showed initial burst release but slower release as the experiment continued. Microspheres made up of combination of the aforementioned two polymers had instant, sharp and burst drug release. Surprisingly there was no absorption after intranasal delivery of chitosan-PVA microspheres in groups of rats comparing to formulated chitosan microspheres having profound absorption due to their smaller particle size, slower drug release rate and better mucoadhesive properties. Therefore, significant reduction in the plasma blood glucose level for chitosan based optimized formulation was seen right after 4.5 hours compared with control group. The aim of the present study was to fabricate an appropriate application of polymeric microspheres for intranasal delivery of insulin using a novel optimized formulation based on industrial level spray drying technique and to realize the possible barriers in scale up process of its large scale production, considering the effectiveness of polyvinyl alcohol (PVA) and chitosan to increase mucoadhesivness, gelling ability and ultimately effective release behavior pattern of insulin. According to this study, the combination of the polymers used and the mean particle size of formulated microspheres were found to be key factors in insulin drug release resulting for further enhancement of insulin absorption via intranasal route of delivery