Sorbitan monostearate/polysorbate 20 organogels containing niosomes: a delivery vehicle for antigens?

Multi-component organogels formed using the non-ionic surfactant sorbitan monostearate as gelator have been formulated to contain niosomes. The purpose of this study was to evaluate the potential of these vesicle-in-water-in-oil (v/w/o) gels as delivery vehicles for vaccines. Bovine serum albumin (BSA) and haemagglutinin (HA) were used as model antigens in depot and immunogenicity studies respectively. The complex gels were prepared by the addition of a hot (60 degrees C) aqueous niosome suspension (v/w) to the sol phase (o, an organic solution of the gelator); a vesicle-in-water-in-oil (v/w/o) emulsion was produced which cools to an opaque, semi-solid, thermoreversible v/w/o gel. Light microscopy of the organogel revealed that the microstructure consists of a tubular network of surfactant aggregates in the organic medium, the niosome suspension being dispersed in these surfactant tubules. Therefore, in such gels, the vaccine is thought to be entrapped in the niosomes, themselves located within the sorbitan monostearate tubular network in the organic medium. In vivo, a depot effect was observed following intramuscular administration of the gel containing the entrapped bovine serum albumin, cleared from the injection site over a period of days. The relatively short-lived nature of the depot was thought to arise due to interactions between the gel and the local interstitial fluid which results in gel disintegration in situ. Thus, the niosomes containing antigens are believed to be released from the organic gel. Immunogenicity studies showed that the v/w/o gel as well as one of the controls, the water-in-oil (w/o) gel, possess immunoadjuvant properties and enhance the primary and secondary antibody titres (of total IgG, IgG1, IgG2a and IgG2b) to haemagglutinin antigen. As far as humoral immunity is concerned, the w/o gel showed stronger immunoadjuvant properties compared to the v/w/o gel, being effective at a lower antigen dose i.e 0.1 microg HA.     

Release of 5-fluorouracil from intramuscular w/o/w multiple emulsions

Comparative in vivo studies of aqueous solution, multiple w/o/w, and w/o emulsions showed that formulating 5-fluorouracil in emulsion systems significantly sustained the release of the drug from intramuscular injection sites in the rat. Intramuscular injection of the drug in both w/o and w/o/w emulsion systems produced sustained blood concentrations with a later blood level peak than observed following intramuscular injection of aqueous solutions of the drug. The multiple w/o/w emulsion exhibited a more rapid release of drug from the injection site than the w/o emulsion because of partitioning of the drug to the external aqueous phase during secondary emulsification. The fate of the oil phase following intramuscular injection of a water/hexadecane/water multiple emulsion spiked with 1-14C-hexadecane has been studied in rats as a function of stabilizer concentrations. Increasing the lipophilic surfactant (Span 80) concentration facilitated the clearance of the oily vehicle from the injection site, by mechanisms which remain to be elucidated.     

Enhanced ocular bioavailability of fluconazole from niosomal gels and microemulsions: formulation,optimization, and in vitro–in vivo evaluation

Fungal keratitis may cause vision loss if it is not treated. Methods other than ocular delivery exhibited several limitations. No previous studies investigated and compared ocular bioavailability of fluconazole (FLZ) from niosomal gels and microemulsions. Niosomal gels of FLZ (0.3% w/w) based on Span^® 60 and cholesterol (CH) using 1% w/w carbopol^® 934 (CP) were evaluated. FLZ microemulsions (0.3% w/v) containing isopropyl myristate (IPM, as oil phase) and a 3:1 mixture of Tween^® 80 (as surfactant) and polyethylene glycol 400 (PEG 400, as cosurfactant) were characterized. Optimized formulations were compared for their ocular bioavailability in rabbit’s. Nanoscopic niosomes (63.67–117.13?nm) and microemulsions (57.05–59.93?nm) showed respective negative zeta potential ranges of ?45.37 to ?61.40 and ?20.50 to ?31.90?mV and sustained release up to 12?h. Entrapment efficiency (EE%) of niosomes ranged from 56.48% to 70.67%. Niosomal gels were more sustainable than niosomes and microemulsions. The most stable niosomal gel based on Span^® 60 and CH at a molar ratio of 5:5 and microemulsion containing 45% w/w IPM and 40% w/w of 3:1 Tween^® 80-PEG 400 mixture significantly (p?<?0.0001) enhanced FLZ ocular bioavailability compared with its solution. Niosomal gel showed higher bioavailability than microemulsion by ≈2-fold.     

Microencapsulation with carrageenan-locust bean gum mixture in a multiphase emulsification technique for sustained drug release

Abstract

A multiphase emulsification technique was modified in this process of microencapsulating gentamicin sulphate, thus avoiding the necessity for a surfactant in preparing the secondary emulsion for a W/O/W emulsion. Various proportions of iota-carrageenan (i-C) and locust bean gum (LBG) were investigated for the W/O/W emulsion after forming the primary W/O emulsion with sorbitan trioleate, Span 85. Upon removal of the oil phase (chloroform) from the W/O/W emulsion by heating (60-65°C), microcapsules or ‘W/W particles containing drug dissolved in sodium hyaluronate were spontaneously formed. These were dispersed in a solution of a mixture of 5-10 per cent w/v polyvinyl alcohol, PVA (average MW 50000-106000; 98 per cent hydrolysed) and 3 per cent v/v polyethylene glycol 200 (PEG 200), and dried to form the hydrogel film casts. Our in vitro experiments in isotonic phosphate buffer solution (pH 7-4) at 37°C., showed that the release of gentamicin sulphate was dependent on concentration of LBG, and concentration or molecular weight of PVA. With the exception of PVA hydrogel matrix preparations containing 20 per cent w/v LBG, all other formulations showed a significant initial ‘burst' release of drug within 6h. The drug-containing microcapsules in the PVA hydrogel film with 20 per cent w/v LBG, exhibited an almost zero-order release of drug up to 140h. It is postulated that an effective barrier or high-density membrane enveloping the microcapsules was formed between i-C and LBG because of their unique molecular configurations. This phenomenon, together with the possible adsorption of i-C molecules at the transient oil and outer aqueous phase interface, presumably eliminated the need for a permanent oil phase and/or an O/W surfactant normally required for preparing W/O/W emulsions.     

Preparation and Evaluation of Multiple Emulsions Water-in-oil-in-water (w/o/w) as Delivery System for Influenza Virus Antigens

In this study, investigations have been carried out to prepare adjuvant active delivery systems; multiple water-in-oil-in-water (w/o/w) emulsion formulations, containing influenza virus surface antigen Hemagglutinin (HA). A modified two-stage emulsification method has been used to prepare multiple emulsions. After improving multiple (w/o/w) emulsion formulations; F1: purified antigen solution (PAS)/soybean oil, HCO-40 and span 80/pluronic F-68, F2: PAS and HPβCD/soybean oil, HCO-40 and span 80/pluronic F-68, F3: PAS/squalane, HCO-40 and span 80/pluronic F-68, formulations were selected for the stability study that continued for a 3 month duration. To evaluate the stability of these formulations, microscopic observation, osmolarities of the internal and external aqueous phases, pH, globule size and viscosity were determined. SDS-PAGE (silver staining) was used to evaluate HA and the micro-bicinchoninic acid (mBCA) assay was used to determine the in vitro release of antigen from formulations. Immune responses of formulations were investigated in Wistar Albino rats and compared with the immune response raised against the conventional vaccine. These responses were detected with Hemagglutination Inhibition (HAI) assay.

The results of this study demonstrated that HA was well entrapped in the multiple (w/o/w) emulsion formulations. Molecular weight and antigenicity of the entrapped HA were not affected by the emulsification procedure. These results suggest that multiple emulsion formulations entrapping influenza antigen may have potential for immunization studies as one of the vaccine delivery system with adjuvant properties.     

Vesicular aceclofenac systems: A comparative study between liposomes and niosomes

Vesicular delivery systems have been reported to serve as local depot for sustained drug release. Aceclofenac multilamellar liposomes and niosomes were prepared and a comparative study was done between them through evaluation of entrapment efficiency, particle size, shape, differential scanning calorimetry and in vitro drug release. A stability study was carried out by investigating the leakage of aceclofenac and the change in the vesicles particle size when stored at (2–8°C) for 3 months. The anti-inflammatory effect of aceclofenac vesicles was assessed by the rat paw oedema technique. Results showed that the entrapment efficiency and the in vitro release of aceclofenac from the vesicles can be manipulated by varying the cholesterol content, the type of surfactant as well as the type of charge. Niosomes showed better stability than liposomes. Both vesicular systems showed significant sustained anti-inflammatory activity compared to the marketed product, with niosomes being superior to liposomes as manifested by both oedema rate and inhibition rate percentages suggesting their effectiveness as topical anti-inflammatory delivery systems.     

Pharmacokinetics of Vancomycin after Intravenous Administration of a W/O/W Emulsion to Rats

A stable water-in-oil-in-water multiple emulsion (w/o/w emulsion) was prepared, and its potential for drug delivery was evaluated. W/o/w emulsions were prepared using a Lipiodol Ultra-Fluid(r) and isopropyl myristate oil mixture for the oily phase and vancomycin (VCM) for the entrapped drug. The surfactants, HCO-40 (5% [w/v]) and Pluronic F-88 were dissolved in the oily phase and the external aqueous phase, respectively. Resultant w/o/w emulsions were evaluated for entrapment efficiency, particle size, viscosity, drug release in vitro, and disposition kinetics of the drug and the w/o/w emulsion in vivo. The particle size of the w/o/w emulsion decreased with an increase in the concentration of F-88 in the external aqueous phase and stirring speed at the second emulsification stage (the smallest being 2.9 ± 1.5 μm). Entrapment efficiency of VCM in the w/o/w emulsion decreased with an increase in the concentration of F-88 (the maximum being 65.3 ± 5.4%). VCM release from the w/o/w emulsion was prolonged and tended to be slower with an increase in the particle size of the emulsion. After intravenous administration, significant differences in pharmacokinetic parameters, such as k₂₁, k_elβ, AUC₀-±, MRT₀-₆, and MRT₀-±, were observed between the VCM solution and the w/o/w emulsion-entrapped drug. When the w/o/w emulsion with Sudan II in the oily phase was administered intravenously, the emulsion accumulated in the lung at first (the highest value was observed just after administration) and then in the liver (the highest value was observed at 60 min). The w/o/w emulsion prepared in this study is expected to be a possible carrier for the prolonged release of water-soluble drugs after intravenous administration.     

Design and in vitro characterization of small unilamellar niosomes as ophthalmic carrier of dorzolamide hydrochloride

Abstract

The objective of this work was to formulate and characterize non-ionic surfactant vesicles (niosomes) as an ocular carrier of dorzolamide hydrochloride (Dorzo); one of the antiglaucoma drugs. Niosomes were prepared of Cholesterol (Chol) with sorbitan monoesters (Span 20, 40, 60) or sorbitan trioleate (Span 85) in a molar ratio of 40:150. Those prepared from Span 40 were selected for further investigation on the effect of addition of dicetylphosphate (DCP) and polyoxyethylene fatty acid esters (either Tween 20, 40 or 80). All The batches were prepared using mechanical shaking technique, followed by sonication and then characterized using Zetasizer, transmission electron microscopy (TEM), calculating percent drug entrapment efficiency and cumulative percent released. Z-average sizes of the niosomes were between 25.9 and 165.5?nm. All niosomal formulations showed negative zeta potential charge. Dorzo was successfully entrapped in all of the formulations with entrapment efficiencies ranging between 34.81% and 97.66%. With reference to release profiles, Dorzo-loaded niosomal formulations showed significant reduction in cumulative percent drug released than Dorzo solution. High entrapment efficiencies, biphasic prolonged release rate and small particles size highlight Dorzo-loaded niosomal preparations as a promising ophthalmic carrier to prolong the drug lowering effect on the intraocular pressure.     

Evaluation of zidovudine encapsulated ethylcellulose microspheres prepared by water-in-oil-in-oil (w/o/o) double emulsion solvent diffusion technique

The preparation of zidovudine-loaded ethylcellulose microspheres by w/o/o double emulsion solvent diffusion method with high entrapment capacity and sustained release is described. A mixed solvent system (MSS) consisting of acetonitrile and dichloromethane in a 1:1 ratio and light liquid paraffin was selected as primary and secondary oil phases, respectively. Span 80 was used as the secondary surfactant for stabilizing the external oil phase. Spherical free flowing microspheres were obtained. The prepared microspheres were characterized by entrapment efficiency, in vitro release behavior, differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The drug-loaded microspheres showed 32 - 55% entrapment capacity. The in vitro release profile could be altered significantly by changing various processing and formulation parameters to give sustained release of drug from the microspheres. The DSC thermograms confirmed the absence of any drug-polymer interaction. SEM studies showed that the microspheres were spherical and porous in nature. The in vitro release profiles from microspheres of different polymer-drug ratios were best fitted to Higuchi model with high correlation coefficient and the n value obtained from Korsmeyer-Peppas model was ranged between 0.23 - 0.54. The drug release was found to be diffusion controlled mechanism.     

Formulation and evaluation of metformin hydrochloride-loaded niosomes as controlled release drug delivery system

Abstract

Lactic acidosis is a serious, metabolic complication that may occur due to metformin hydrochloride (MH) accumulation during the treatment of diabetes mellitus. The aim of this study is to enhance the bioavailability of MH by oral route. Span 40 and cholesterol were used for the preparation of MH-loaded niosomes by the reverse phase evaporation technique. Dicetyl phosphate (DCP) and 1,2-dioleoyl-3-trimethylammonium-propane chloride salt (DOTAP) were used to obtain negatively and positively charged vesicles, respectively. The mean particle size ranged from 223.5 to 384.6?nm and the MH-loaded niosomes’ surface was negatively charged in the absence of charge inducing agents (?16.6?±?1.4?mV) and also with DCP (?26.9?±?1.0?mV), while it was positively charged (+8.7?±?1.2?mV) with DOTAP. High entrapment efficiency was observed in all the formulations. MH-loaded niosomes were found to effectively sustain the release of drug, particularly with positively charged niosomes. The bioavailability of MH-loaded niosomes was assessed by measuring the serum values of glucose and metformin in the different studied Wistar rats groups. The pharmacokinetic data of MH-loaded niosomal preparation showed a significant prolongation and increased intensity of hypoglycemic effect more than that observed for free MH solution. Area above the blood glucose levels–time curve (AAC), maximum hypoglycemic response and time of maximum response (T_max) were significantly higher (p?<?0.001) when MH was administered in niosomal form compared to free drug solution. It could be concluded that MH-loaded niosome is promising extended-release preparation with better hypoglycemic efficiency.     

Preparation and evaluation of multiple emulsions water-in-oil-in-water (w/o/w) as delivery system for influenza virus antigens

In this study, investigations have been carried out to prepare adjuvant active delivery systems; multiple water-in-oil-in-water (w/o/w) emulsion formulations, containing influenza virus surface antigen Hemagglutinin (HA). A modified two-stage emulsification method has been used to prepare multiple emulsions. After improving multiple (w/o/w) emulsion formulations; F1: purified antigen solution (PAS)/soybean oil, HCO-40 and span 80/pluronic F-68, F2: PAS and HPbetaCD/soybean oil, HCO-40 and span 80/pluronic F-68, F3: PAS/squalane, HCO-40 and span 80/pluronic F-68, formulations were selected for the stability study that continued for a 3 month duration. To evaluate the stability of these formulations, microscopic observation, osmolarities of the internal and external aqueous phases, pH, globule size and viscosity were determined. SDS-PAGE (silver staining) was used to evaluate HA and the micro-bicinchoninic acid (mBCA) assay was used to determine the in vitro release of antigen from formulations. Immune responses of formulations were investigated in Wistar Albino rats and compared with the immune response raised against the conventional vaccine. These responses were detected with Hemagglutination Inhibition (HAI) assay. The results of this study demonstrated that HA was well entrapped in the multiple (w/o/w) emulsion formulations. Molecular weight and antigenicity of the entrapped HA were not affected by the emulsification procedure. These results suggest that multiple emulsion formulations entrapping influenza antigen may have potential for immunization studies as one of the vaccine delivery system with adjuvant properties.     

Encapsulation of water-soluble drugs by an o/o/o-solvent extraction microencapsulation method

A new o/o/o-solvent extraction microencapsulation method based on less toxic solvents is presented in this study. The drug is dissolved/dispersed into a poly(D,L-lactide)/or poly (D,L-lactide-co-glycolide) (PLGA) solution in a water-miscible organic solvent (e.g., dimethylsulfoxide or 2-pyrrolidone) (o(1)), followed by emulsification into an oil phase (o(2)) (e.g., peanut oil). This emulsion is added to the external phase (o(3)) to solidify the drug-containing polymer droplets. The polymer solvent and the oil are extracted in an external phase (o(3)) (e.g., ethanol), which is a nonsolvent for the polymer and miscible with both the polymer solvent and the oil. One major advantage of this method is the reduced amount of solvent/nonsolvent volumes. In addition, very high encapsulation efficiencies were achieved at polymer concentration of 20%, w/w for all investigated polymers and o(1)/o(2) phase ratios with ethanol as the external (o(3)) phase. The encapsulation efficiency was very low (<20%) with water as external phase. The particle size of the microparticles increased with increasing polymer concentration and o(1)/o(2) phase ratio and larger microparticles were obtained with 2-pyrrolidone compared to dimethylsulfoxide as polymer solvent (o(1)). After an initial burst, in vitro drug release from the microparticles increased for the investigated polymer as follows: Resomer(?) RG 506>RG 756>R 206. A third more rapid release phase was observed after 6 weeks with Resomer(?) RG 506 due to polymer degradation. Similar drug release patterns were obtained with the o/o/o and w/o/w multiple emulsion methods because of similar porous structures. This new method has the advantages of less toxic solvents, much lower preparation volume and solvent consumption and high encapsulation efficiencies when compared to the classical w/o/w method.     

Encapsulation of BSA using a modified W/O/O emulsion solvent removal method

A systematic investigation of protein encapsulation in polylactic-co-glycolic-acid (PLGA) was carried out using the formation of a w/o/o emulsion followed by solvent removal. Various factors were studied, including composition of the suspension medium and the relative amounts of aqueous phase containing protein to polymer solution. High yields of microsphere fabrication were achieved by using silicon oil containing methylene chloride as a suspension medium instead of pure silicon oil, with minimal loss of polymer and protein drug (<2%). The amount of aqueous phase influenced the process and successful encapsulation was obtained if the volume ratios of aqueous phase to polymer solution were less than 5% (v/v) at a wide range of polymer concentration (2-15% g ml-1). Protein encapsulation by this w/o/o emulsion and solvent removal method has a high yield of microsphere fabrication and protein encapsulation (98%). In addition, it provides an easy way to control the release rate of protein encapsulated in microspheres by modulating their porosity in fabrication process.     

Effect of Nonionic Surfactant on Transport of Model Drugs in Emulsions

Purpose. To investigate the influence of excess surfactant on transport kinetics in emulsions, using phenylazoaniline (PAA), benzocaine, benzoic acid and phenol as model drugs. Mineral oil was chosen as the oil phase and the nonionic surfactant, polyoxyethylene oleyl ether (Brij 97) as the emulsifier. Methods. Model drug transport in emulsions was investigated using side by side diffusion cells mounted with hydrophilic dialysis or hydrophobic membranes. A novel method, involving a combination of a membrane equilibrium technique and surface tension measurement (Wilhelmy plate method), was developed to determine surfactant critical micelle concentration (CMC) in the presence of O/W emulsions. Emulsion stability was determined by droplet size analysis as a function of time, temperature and dilution using photon correlation spectroscopy and a light blockage technique. Model drug mineral oil/water partition coefficients and aqueous solubilities were determined in the presence of surfactant. Results. The emulsion CMC value was used to calculate micellar phase concentration. The transport rates of PAA and benzocaine in emulsions increased with increase in Brij 97 micellar concentration up to 1.0 % w/v and then decreased at higher surfactant concentrations. The transport rates of the more hydrophilic compounds, benzoic acid (ionized form, pH 7.0) and phenol, were not affected by the presence of micellar phase. Conclusions. Excess surfactant affected the transport rates of the model drugs in the emulsions depending on drug lipophilicity. Transport rates measured using side by side diffusion cells appeared to be governed by model drug partitioning rates from the oil to the continuous phases and by membrane type.     

SEM Imaging Predicts Quality of Niosomes from Maltodextrin-Based Proniosomes

Purpose. The limits to surfactant loading of proniosomes were determined and a rationale developed for the observed relationship between the composition of proniosomes and the quality of reconstituted niosome suspension. Methods. A novel method for producing proniosomes with a maltodextrin carrier was recently developed, which provides for rapid reconstitution of niosomes with minimal residual carrier. A slurry of maltodextrin and surfactant was dried to form a free–flowing powder which could be rehydrated by addition of warm water. This method provided facile production of a wide range of proniosome compositions, and thus, allowed us to examine rehydration behavior for similar concentrations of surfactant over a wide range of film thickness. SEM images of proniosomes with various degrees of surfactant loading and images of pure surfactant were compared. Direct observation and particle size measurements by laser light scattering provided characterization of the final niosome preparations. Results. Successful rehydration of surfactant to produce niosomes from dried film requires that the film be as thin as possible to avoid the clumping and precipitation that occurs when pure, granular surfactant is hydrated directly. The appearance of a coarse, broken surface on the proniosomes correlates with inefficient rehydration and occurrence of aggregation and precipitate in the final niosome suspension. Conclusions. These observations provide an indication of the requirements for dry proniosomes to yield niosome suspensions of high quality.     

Encapsulation of BSA using a modified W/O/O emulsion solvent removal method

A systematic investigation of protein encapsulation in polylactic-co-glycolic-acid (PLGA) was carried out using the formation of a w/o/o emulsion followed by solvent removal. Various factors were studied, including composition of the suspension medium and the relative amounts of aqueous phase containing protein to polymer solution. High yields of microsphere fabrication were achieved by using silicon oil containing methylene chloride as a suspension medium instead of pure silicon oil, with minimal loss of polymer and protein drug (<2%). The amount of aqueous phase influenced the process and successful encapsulation was obtained if the volume ratios of aqueous phase to polymer solution were less than 5% (v/v) at a wide range of polymer concentration (2–15%?g?ml^?1). Protein encapsulation by this w/o/o emulsion and solvent removal method has a high yield of microsphere fabrication and protein encapsulation (98%). In addition, it provides an easy way to control the release rate of protein encapsulated in microspheres by modulating their porosity in fabrication process.     

Polyhedral Non-ionic Surfactant Vesicles

Large polyhedral (2–10 μm) non-ionic surfactant vesicles (niosomes) formed from mixtures of a hexadecyl diglycerol ether (C₁₆G₂), a cholesteryl poly-24-oxyethylene ether (solulan C24) and a low level of cholesterol are being investigated as slow-release systems for ophthalmic, subcutaneous or intramuscular administration. The phase-diagram of this three-component system has been constructed and these polyhedral vesicles are found to be in the gel (L_β) phase. Confocal laser-scanning microscopy was used to confirm the complex morphology of these vesicles. The thermo-responsive nature of release of entrapped carboxyfluorescein and nicotinamide adenine dinucleotide has been studied; release is increased with increase in temperature (37°C) even though the polyhedral vesicles still maintain their polyhedral shape at this temperature. The results indicate that the thermo-responsive features of the niosomes are a result of reversible changes in bi-layer permeability caused by temperature-mediated alteration in the membrane-packing characteristics of the polyethoxylated cholesterol ether.     

Formulation and in vitro evaluation of ethyl cellulose microspheres containing zidovudine

The aim of this study was to formulate and evaluate microencapsulated controlled release preparations of zidovudine using ethyl cellulose as the retardant material with high entrapment efficiency and extended release. Microspheres were prepared by water-in-oil-in-oil (w/o/o) double emulsion solvent diffusion method. A mixed solvent system (MSS) consisting of acetonitrile and dichloromethane in a 1:1 ratio and light liquid paraffin were chosen as primary and secondary oil phases, respectively. Span 80 was used as the surfactant for stabilizing the secondary oil phase. The prepared microspheres were white, free flowing and spherical in shape and characterized by drug loading, infrared spectroscopy (IR), differential scanning colorimetry (DSC) and scanning electron microscopy (SEM). The in vitro release studies were performed using PH 7.4 phosphate buffer. The drug loaded microspheres showed 41–55% of entrapment and release was extended up to 18–20?h. The infrared spectra and DSC and DTA thermograms showed stable character of zidovudine in the drug loaded microspheres and revealed the absence of drug-polymer interactions. SEM studies showed that the microspheres are spherical and porous in nature. Data obtained from in vitro release were fitted to various kinetic models and high correlation was obtained in the Higuchi model. The drug release was found to be diffusion controlled.     

Glucosamine-anchored doxorubicin-loaded targeted nano-niosomes: pharmacokinetic,toxicity and pharmacodynamic evaluation

Background: Efficacy of anticancer drug is limited due to non-selectivity and toxicities allied with the drug; therefore the heart of the present work is to formulate drug delivery systems targeted selectively towards cancer cells with minimal toxicity to normal cells.

Purpose: Targeted drug delivery system of doxorubicin (DOX)-loaded niosomes using synthesized N-lauryl glucosamine (NLG) as a targeting ligand.

Methods: NLG-anchored DOX niosomes were developed using ethanol injection method.

Results: Developed niosomes had particle size <150?nm and high entrapment efficiency ～90%. In vivo pharmacokinetics exhibited long circulating nature of targeted niosomes with improved bioavailability, which significantly reduced CL and Vd than DOX solution and non-targeted niosomes (35 fold and 2.5 fold, respectively). Tissue-distribution study and enzymatic assays revealed higher concentration of DOX solution in heart while no toxicity to major organs with developed targeted niosomes was observed. Solid skin melanoma tumor model in mice manifested the commendable targeting potential of targeted niosomes with significant reduction in tumor volume and high % survival rate without drop in body weight in comparison with DOX solution and non-targeted niosomes of DOX.

Conclusion: The glucosamine-anchored DOX-loaded targeted niosomes showed its potential in cancer targeted drug therapy with reduced toxicity. Abbreviations ALT alanine transaminase

CL clearance

CPK creatinine phosphokinase

DOX doxorubicin

EDC.HCL ethyl carbidimide hydrochloride

GLUT glucose transporter

GSH glutathione S-transferase

LDH lactate dehydrogenase

LHRH luteinizing hormone-releasing hormone

MDA malonaldehyde

NHS N-hydroxy succinimide

NLG N-lauryl glucosamine

NTAR DoxNio non-targeted doxorubicin niosomes

PBS phosphate buffer saline

RGD argynyl glycyl aspartic acid

SGOT serum glutamate oxaloacetate transaminase

SGPT serum glutamate pyruvate transaminase

SOD superoxide dismutase

TAR DoxNio targeted doxorubicin niosomes

Vd volume of distribution

     

Preparation and in vitro evaluation of ethyl cellulose microspheres containing stavudine by the double emulsion method

The aim of this study was to formulate and evaluate microspheres of stavudine by water-in-oil-in-oil (w/o/o) double emulsion solvent diffusion method using ethyl cellulose and ethyl cellulose in combination with polyvinyl pyrrolidone. A mixed solvent system consisting of acetonitrile and dichloromethane in an 1: 1 ratio and light liquid paraffin was chosen as primary and secondary oil phase, respectively. Span 80 was used as surfactant for stabilizing the secondary oil phase. The influence of formulation factors like stirring speed, surfactant concentration on particle size and polymer:drug ratio and combination of polymers on drug release characteristics of the microspheres was investigated. The prepared microspheres characterized by micrometric properties, drug loading, Fourier transform infrared spectroscopy, X-ray powder difractometry and scanning electron microscopy. The prepared microspheres were white, free flowing and spherical in shape, stable in nature, with 41-65% of drug entrapment efficiency. The best-fit release kinetics was achieved with Higuchi plot followed by first order and zero order. The release of stavudine was influenced by the drug to polymer ratio, particle size and polymer combination.