Oestradiol skin delivery from ultradeformable liposomes: refinement of surfactant concentration

The aims of this study were to refine ultradeformable liposomes for oestradiol skin delivery and to evaluate Span 80 and Tween 80 as edge activators compared with sodium cholate. Vesicles containing phosphatidylcholine (PC) mixed with edge activators and oestradiol were prepared. Entrapment efficiency and vesicle size were determined. Interactions between activators and vesicles were investigated using differential scanning calorimetry. Transepidermal permeation of oestradiol from vesicles was studied compared to saturated aqueous control in vitro. The maximum flux (J(max)) and its time (T(max)) were calculated from the flux curves and skin deposition was assessed. The compositions of refined formulations were predicted, liposomes prepared, and tested against control. Entrapment efficiency depended on PC concentration with some contribution from sodium cholate and Tween 80. Vesicle sizes ranged from 124 to 135 nm. Edge activators interacted with lipid bilayers and disrupted packing. The refined edge activator concentrations in PC vesicles were 14.0, 13.3 and 15.5% w/w for sodium cholate, Span 80 and Tween 80, respectively; they increased J(max) by 18, 16 and 15-fold and skin deposition by 8, 7 and 8-fold compared with control. Ultradeformable vesicles thus improved skin delivery of oestradiol compared to control and Span 80 and Tween 80 were equivalent to sodium cholate as edge-activators.     

In-vitro release of diclofenac diethylammonium from lipid-based formulations

This article presents the preparation and topical performance of some new lipid-based formulations of diclofenac, namely (a) a diclofenac aqueous gel containing mixed micelles (sodium cholate:egg lecithin molar ratio 0.55); (b) diclofenac lotion that contains soya lecithin, ethanol and buffer; and (c) diclofenac lipogel containing egg lecithin, isopropyl myristate, propylene glycol and ethanol. Gel formulations were prepared using Carbomer 934. Release of diclofenac from all formulations was monitored via dialysis through Spectra/por membrane into phosphate buffer (0.2 M pH=7.4) using a Franz cell. Drug release profile and diffusion coefficients were compared with brand formulation (Geigy's Vlotaren Emulgel). Statistical analysis of data show that the diffusion coefficient of the drug from these formulations rank according to the following order: Diclofenac lotion (D=5.308x10(-7) cm(2)/s) >lipogel (D=2.102 x 10(-7) cm(2)/s) >Voltaren Emulgel (1.518 x 10(-7) cm(2)/s) >aqueous gel mixed micelle (0.966 x 10(-7) cm(2)/s). These results show that diclofenac lotion and lipogel maybe more suitable formulations than the conventional topical dosage form.     

Lecithin vesicular carriers for transdermal delivery of cyclosporin A

Two kinds of vesicles with and without the presence of sodium cholate (flexible vesicles and conventional vesicles) were prepared, using cyclosporin A as model drug. When applied onto the excised abdominal skin of mice non-occlusively, the enhancing effects of vesicles on the penetration of cyclosporin A were assessed by an in vitro permeation technique. The effect of sodium cholate micelles was also studied. In vivo study was carried out by topical application of vesicles onto the mice skin and drug serum concentration was detected. Results showed that after 8 h of administration, flexible vesicles transported 1.16 microg of cyclosporin A through per cm(2) mice skin and amounted to 1.88 microg 24 h later. The residual amount in the skin was 1.78+/-0.51 microg/cm(2). However, flexible vesicles failed to transport measurable amount of drug through pre-hydrated skin while deposited 2.39+/-0.26 microg/cm(2) into the skin. Conventional vesicles failed to transfer cyclosporin A into the receiver while accumulated 0. 72+/-0.19 microg/cm(2) of drug in the skin. Furthermore, 1 and 40% sodium cholate micelles precluded the transport of cyclosporin A. In vivo studies indicated that with the application of flexible vesicles, serum drug concentration of 53.43+/-9.24 ng/ml was detected 2 h later. After the stratum corneum of mouse skin has been destroyed by shaving, flexible vesicles transferred large amount of drug into blood, up to 187.32+/-53.21 ng/ml after 1 h of application. Conventional vesicles failed to deliver measurable amount of drug into the blood under normal skin condition. In conclusion, flexible vesicle is better than conventional vesicle as the carrier for transdermal delivery of cyclosporin A. Penetration and fusion have been suggested to be two major functional mechanisms. Hydration is detrimental to the enhancement effect. Stratum corneum constitutes main barrier to the transport of lipophilic cyclosporin A.     

Deformable liposomes and ethosomes as carriers for skin delivery of ketotifen

Deformable liposomes and ethosomes were investigated as carriers for skin delivery of ketotifen (KT) in terms of vesicle size, entrapment efficiency, stability, in vitro permeation and skin deposition properties. Phosphatidylcholine (PC) from soybean lecithin was used in the preparation of all vesicles. Sodium cholate, sodium deoxycholate and Tween 80 were investigated as edge activators in preparation of KT deformable liposomes. KT ethosomes were prepared in two PC concentrations, 2% and 4.25% w/v, in 30% v/v ethanol. KT deformable liposomes showed improved entrapment efficiency over KT ethosomes. KT deformable liposomes with Tween 80 as an edge activator were more stable upon storage at 5 +/- 1 degree C than those prepared using sodium cholate or sodium deoxycholate and were more stable than KT ethosomes. In vitro permeation and skin deposition studies employed only deformable liposomes with Tween 80 as an edge activator and ethosomes with 4.25% w/v PC concentration. Both of them improved skin delivery of KT over controls and over traditional liposomes, with greater improvement of KT skin deposition than KT skin permeation, hence are more useful for dermal than for transdermal delivery of KT.     

Effect of mixed micelle formulations including terpenes on the transdermal delivery of diclofenac

The significant inhibitory action of diclofenac formulated in mixed micelles of lecithin with cholate or deoxycholate was observed on the rat hind paw edema induced by carrageenan. In the primary stage, mixed micelle formulation of deoxycholate was more effective compared with that of cholate. However, in the final term, the inhibitory action was similar in both formulations. In a previous study, the flux of diclofenac was greater in the mixed micelle formulation of deoxycholate compared with that of cholate. It was suggested that the permeation rate of diclofenac through skin was proportional to the pharmacological activity. The hind paw edema was quickly inhibited when cyclic monoterpene such as d-limonene or l-menthol was included in the formulations. All the micelle formulations significantly decreased the value of AUC estimated the hind paw thickness-time profile. This suggests that the micelle formulation of cholate in addition to deoxycholate showed significant anti-inflammatory activity to hind paw edema of rats. Incorporation of d-limonene or l-menthol was more effective on the decrease of AUC. A pharmacological study revealed that micelle formulations were able to reduce the skin irritation of chemicals.     

Triamcinolone permeation from different liposome formulations through rat skin in vitro

The permeation of triamcinolone acetonide (TRMA) from various liposome formulations through rat skin was studied in vitro. The penetrated amount, permeability and intradermal retention of TRMA were compared among various lipid compositions, different vesicle sizes (0.2, 0.4 and 1 μm), charges (positive, negative and neutral), as well as between multilamellar vesicles (MLV) and small unilamellar vesicles (SUV). All of the liposome formulations resulted in significantly higher flux and permeability of TRMA than a commercial TRMA ointment. The ‘skin lipid’ liposome provided the most effective transdermal delivery of incorporated TRMA. Presence or absence of cholesterol in the lipid bilayers did not reveal any difference in transdermal delivery of the associated TRMA. The flux and permeability of TRMA through skin were not influenced by the vesicle size of MLV, but was significantly increased by negative SUV. Intradermal retention of TRMA from positive MLV was significantly higher, while that from neutral SUV was significantly lower, than from other formulations. Liposomal lipid was not detectable on the receptor compartment. These results suggest that liposome itself may not penetrate through the skin, but that it does enhance the transfer of incorporated TRMA. Liposomal lipid composition is the most important factor affecting the efficiency of transdermal delivery of incorporated drugs, but was not correlated with its phase transition temperature.     

Skin delivery of oestradiol from deformable and traditional liposomes: mechanistic studies

Deformable vesicles and traditional liposomes were compared as delivery systems for oestradiol to elucidate possible mechanisms of drug delivery through human skin. Accordingly, epidermal permeation of oestradiol from optimized deformable vesicles and traditional liposome formulations was studied under low dose non-occluded conditions. Five mechanisms were investigated. A free drug mechanism compared low-dose permeation through skin with drug release determined after separation of the free drug. Penetration enhancement was researched by studying skin pretreatment with empty vesicles. Improved drug uptake by skin was monitored by dipping stratum corneum into different formulations for 10 min and determining drug uptake. The possibility that intact vesicles permeate through the epidermis was tested by comparing permeation from 136-nm vesicles with that from >500-nm vesicles, assuming that penetration depends on vesicle size. The possibility that different entrapment efficiencies in alternative formulations could be responsible for the difference in delivery was also evaluated. Lipid vesicles improved the skin delivery of oestradiol compared with delivery from an aqueous control. Maximum flux (Jmax) was increased 14- to 17-fold by use of deformable vesicles and 8.2- to 9.8-fold by use of traditional liposomes. Deformable vesicles were thus superior to traditional liposomes. Drug release was negligible over the period during which skin flux was maximum. Pretreatment with empty vesicles resulted in an enhancement ratio of 4.3 for pure phosphatidylcholine (PC) vesicles but the enhancement ratio ranged from only 0.8 to 2.4 for other formulations. Vesicles increased drug uptake into the stratum corneum 23- to 29-fold. Relative flux values obtained from small and large vesicles were similar. No correlation was found between entrapment efficiency and skin delivery. The results showed no evidence of a free drug mechanism, but revealed a possible penetration-enhancing effect for pure PC vesicles, although this was not the only mechanism operating. The positive uptake suggested that lipid vesicles increased drug partitioning into the skin. The data provided no evidence for in-vitro liposome penetration through skin as distinct from vesicle penetration into the stratum corneum.     

Dermal delivery of selected hydrophilic drugs from elastic liposomes: effect of phospholipid formulation and surfactants

The effect of phospholipid formulation and choice of surfactant on skin permeation of selected hydrophilic drugs from elastic liposomes across human epidermal membrane has been studied. Sodium cholate and various concentrations of phosphatidylcholine were used for the preparation of liposomes namely hydrogenated phosphatidylcholine 90% (Phospholipon 90H), phosphatidylcholine 95% (Phospholipon 90G), phosphatidylcholine 78.6% (Phospholipon 80), and phosphatidylcholine 50% (Phosal PG). To investigate the effect of the surfactant, liposomes were prepared from 95% phosphatidylcholine (Phospholipon 90G) and various surfactants (sodium cholate, sodium deoxycholate, Span 20 (sorbitan monolaurate), Span 40 (sorbitan monopalmitate), Span 60 (sorbitan stearate) and Span 80 (sorbitan monooleate)). The vesicles were prepared by the conventional rotary evaporation technique. The film was hydrated with phosphate-buffered saline (10 mL) containing 9, 2 and 2.5 mg mL(-1) of methotrexate, idoxuridine and aciclovir, respectively. All formulations contained 7% ethanol. Homogenously-sized liposomes were produced following extrusion through 100-nm polycarbonate filters using Lipex Extruder. Particle size was characterized by transmission electron microscopy. Vertical Franz diffusion cells were used for the study of drug delivery through human epidermal membrane. For the three drugs, the highest transcutaneous fluxes were from elastic liposomes containing 95% phosphatidylcholine. In general, a higher flux value was obtained for liposomes containing sodium cholate compared with sodium deoxycholate. For the liposomes containing sorbitan monoesters, there was no clearly defined trend between alkyl chain length and flux values. Overall, transcutaneous fluxes of liposomal preparations of hydrophilic drugs were comparable with those from saturated aqueous solutions (P > 0.05).     

Penetration enhancer-containing vesicles (PEVs) as carriers for cutaneous delivery of minoxidil

The aim of this work was to evaluate the ability of a few different penetration enhancers to produce elastic vesicles with soy lecithin and the influence of the obtained vesicles on in vitro (trans)dermal delivery of minoxidil. To this purpose, so-called Penetration Enhancer-containing Vesicles (PEVs) were prepared as dehydrated–rehydrated vesicles by using soy lecithin and different amounts of three penetration enhancers, 2-(2-ethoxyethoxy)ethanol (Transcutol^®), capryl-caproyl macrogol 8-glyceride (Labrasol^®), and cineole. Soy lecithin liposomes, without penetration enhancers, were used as control. Prepared formulations were characterized in terms of size distribution, morphology, zeta potential, and vesicle deformability.The influence of PEVs on (trans)dermal delivery of minoxidil was studied by in vitro diffusion experiments through newborn pig skin in comparison with traditional liposomes and ethanolic solutions of the drug also containing each penetration enhancer. A skin pre-treatment study using empty PEVs and conventional liposomes was also carried out.Results showed that all the used penetration enhancers were able to give more deformable vesicles than conventional liposomes with a good drug entrapment efficiency and stability. In vitro skin penetration data showed that PEVs were able to give a statistically significant improvement of minoxidil deposition in the skin in comparison with classic liposomes and penetration enhancer-containing drug ethanolic solutions without any transdermal delivery. Moreover, the most deformable PEVs, prepared with Labrasol^® and cineole, were also able to deliver to the skin a higher total amount of minoxidil than the PE alcoholic solutions thus suggesting that minoxidil delivery to the skin was strictly correlated to vesicle deformability, and therefore to vesicle composition.     

Stability of SUV liposomes in the presence of cholate salts and pancreatic lipases: effect of lipid composition.

The effect of bile salts (sodium cholate and sodium taurocholate), and pancreatic lipases on the structural integrity of SUV liposomes of different lipid compositions was studied. Liposomal membrane integrity was judged by bile salt or pancreatin-induced release of vesicle encapsulated 5,6-carboxyfluorescein, and vesicle size distribution before and after incubations. Bile salt concentration was 10 mM, while a saturated solution of pancreatin (mixed with equal volume of liposomes) was utilized. Results agree with earlier studies, demonstrating the instability of liposomes composed of lipids with low transition temperatures (PC and DMPC) in presence of cholates. Addition of cholesterol (1:1 lipid:chol molar ratio) does not substantially increase the encapsulated molecule retention. Nevertheless, liposomes composed of lipids with high transition temperatures (DPPC, DSPC and SM), retain significantly higher amounts of encapsulated material, under all conditions studied. Furthermore, the vesicles formed by mixing cholesterol with these lipids will possibly be sufficiently stable in the gastrointestinal tract for long periods of time. Sizing results reveal that in most cases release of encapsulated molecules is mainly caused by their leakage through holes formed on the lipid bilayer. However, in stearylamine containing DPPC and DSPC vesicles, the cholate-induced drastic decrease in vesicle size suggests total liposome disruption as the possible mechanism of encapsulated material immediate release.     

Sorbitan monopalmitate-based proniosomes for transdermal delivery of chlorpheniramine maleate

A proniosomal gel for transdermal drug delivery of chlorpheniramine maleate (CPM) was developed based on Span 40 and extensively characterized in vitro. The system was evaluated for the effect of composition of formulation, type of surfactants and alcohols on the drug loading, rate of hydration, vesicle size, polydispersity, entrapment efficiency, and drug release across cellulose nitrate dialysis membrane. The stability studies were performed at 4°C and at room temperature. The results showed that lecithin produced more stable and larger vesicles with higher loading efficiency but lower dissolution efficiency than cholestrol (chol) and dicethyl phosphate (DCP). The type of alcohol had no significant effect on the stability of vesicles, but ethanol produced larger vesicles (≈44 μm) and entrapped a greater amount of drug. Drug release from vesicles of lecithin followed a first-order kinetics whereas those with DCP or without lecithin fit better with a Higuchi model. The proniosomes that contained Span 40/lecithin/chol prepared by ethanol showed optimum stability, loading efficiency, and particle size and release kinetic suitable for transdermal delivery of CPM.     

Sorbitan Monopalmitate-Based Proniosomes for Transdermal Delivery of Chlorpheniramine Maleate

A proniosomal gel for transdermal drug delivery of chlorpheniramine maleate (CPM) was developed based on Span 40 and extensively characterized in vitro. The system was evaluated for the effect of composition of formulation, type of surfactants and alcohols on the drug loading, rate of hydration, vesicle size, polydispersity, entrapment efficiency, and drug release across cellulose nitrate dialysis membrane. The stability studies were performed at 4°C and at room temperature. The results showed that lecithin produced more stable and larger vesicles with higher loading efficiency but lower dissolution efficiency than cholestrol (chol) and dicethyl phosphate (DCP). The type of alcohol had no significant effect on the stability of vesicles, but ethanol produced larger vesicles (≈44 μm) and entrapped a greater amount of drug. Drug release from vesicles of lecithin followed a first-order kinetics whereas those with DCP or without lecithin fit better with a Higuchi model. The proniosomes that contained Span 40/lecithin/chol prepared by ethanol showed optimum stability, loading efficiency, and particle size and release kinetic suitable for transdermal delivery of CPM.     

Effect of preparation techniques on the properties of curcumin liposomes: characterization of size, release and cytotoxicity on a squamous oral carcinoma cell line

Curcumin, a chemopreventive agent, was incorporated into liposomes using different preparation techniques and characterized for parameters such as drug loading efficiency, size, in vitro release and in vitro cytotoxicity on a squamous carcinoma cell line. Liposomes were prepared with different methods - thin layer evaporation, ethanol injection and sonication methods, respectively, obtaining, multilamellar vesicles (MLVs) and small unilamellar vesicles (SUVs). The preparation techniques influenced the size, encapsulation efficiency, in vitro release and cytotoxicity profiles. Encapsulation efficiency increased with decrease in drug to lipid ratio in the following rank order - MLVs > SUVs > ethanol injection vesicles. In vitro release and in vitro cytotoxicity were a function of the size of vesicle, which varied depending on the preparation technique. Based on these results, it can be concluded that different liposomal formulations can be employed to achieve unique in vivo needs in cancer chemotherapy.     

A study of the enhanced sensitizing capacity of a contact allergen in lipid vesicle formulations

The growing focus on nanotechnology and the increased use of nano-sized structures, e.g. vesicles, in topical formulations has led to safety concerns. We have investigated the sensitizing capacity and penetration properties of a fluorescent model compound, rhodamine B isothiocyanate (RBITC), when administered in micro- and nano-scale vesicle formulations. The sensitizing capacity of RBITC was studied using the murine local lymph node assay (LLNA) and the skin penetration properties were compared using diffusion cells in combination with two-photon microscopy (TPM).The lymph node cell proliferation, an indicator of a compounds sensitizing capacity, increased when RBITC was applied in lipid vesicles as compared to an ethanol:water (Et:W) solution. Micro-scale vesicles showed a slightly higher cell proliferative response compared to nano-scale vesicles. TPM imaging revealed that the vesicle formulations improved the skin penetration of RBITC compared to the Et:W solution. A strong fluorescent region in the stratum corneum and upper epidermis implies elevated association of RBITC to these skin layers when formulated in lipid vesicles.In conclusion, the results indicate that there could be an elevated risk of sensitization when haptens are delivered in vehicles containing lipid vesicles. Although the size of the vesicles seems to be of minor importance, further studies are needed before a more generalized conclusion can be drawn. It is likely that the enhanced sensitizing capacity is a consequence of the improved penetration and increased formation of hapten-protein complexes in epidermis when RBITC is delivered in ethosomal formulations.     

Formulation optimization of meloxicam sodium gel using response surface methodology

The influences of a combination of different mechanisms of penetration enhancers on the penetration absorption properties of meloxicam sodium formulations through rat skin were investigated using response surface methodology. A uniform design was applied to prepare model formulations systematically that were composed of four independent variables: the content of ethanol (x(1)), propylene glycol (x(2)), menthol (x(3)), and azone (x(4)). The penetration rate (flux) of meloxicam sodium gel through rat skin was chosen as the response which had to be higher than 400microg/hcm(2) the required flux of meloxicam gel to maintain a therapeutic concentration. The result showed optimal formulation could be obtained from this response surface methodology. Menthol had the greatest potential influence on the penetration absorption of meloxicam sodium, followed by azone, ethanol and PG, respectively. By in vivo study, meloxicam could be determined 1h after topical administration and reached steady-state concentration at about 12h. The bioavailability (%) of the optimal meloxicam sodium gel was about 50.1%.     

New insights into the mode of action of ultradeformable vesicles using calcein as hydrophilic fluorescent marker

Whether ultradeformable vesicles pass intact through the stratum corneum and can promote the transdermal absorption of any substance remain open questions. This paper presents different experimental approaches, based on the use of calcein as hydrophilic fluorescent marker, to probe the physicochemical and pharmacokinetic characteristics of these vesicles. Ultradeformable membranes made from natural phosphatidylcholine and sodium cholate were found to be highly permeable to calcein, as a result of the permeabilizing effects of sodium cholate and ethanol. In vitro skin permeation and in vivo transdermal (percutaneous) absorption studies were performed using hairless mice. Both studies indicated that deformable vesicles reduce the transdermal flux of calcein, when compared to a solution containing or not sodium cholate and ethanol. The data support the model that the transdermal absorption of calcein from deformable vesicles is controlled by the release of the drug from the formulation deposited onto the skin surface. Importantly, fluorescence measurements of the receptor fluid of the Franz diffusion cell after addition of Co²⁺ quencher revealed that permeated calcein exists essentially under the non-encapsulated form. In conclusion, our results argue against the model that deformable vesicles would carry hydrophilic drugs across the skin and act as a sustained release system in deep tissues.     

The effect of cholate on solubilisation and permeability of simple and protein-loaded phosphatidylcholine/sodium cholate mixed aggregates designed to mediate transdermal delivery of macromolecules.

Carriers for non-invasive administration of biologically important antioxidant enzymes Cu,Zn-superoxide dismutase (SOD) and catalase (CAT) were developed. Solubilisation and permeabilities of various soybean phosphatidylcholine/sodium cholate (SPC/NaChol) mixtures, mainly in the form of lipid bilayers, focussing on system properties relevant for non-invasive enzyme delivery were investigated in this work. Static and dynamic light scattering measurements gave information on the behaviour of the systems containing up to 40 mM NaChol and 30.6-1.2 mM SPC in the final suspension. The average size of such mixed aggregates was in the 100-200 nm range. Suspension turbidity decreased by 50% upon increasing nominal molar detergent/lipid ratio to NaChol/SPC = 7 and 1.25, in case of SPC = 1.2 and 19.6 mM, respectively. The effective NaChol/SPC molar ratio in bilayers saturated with the detergent was found to be: R(e)(sat) = 0.70 +/- 0.01; bilayer solubilisation point corresponded to R(e)(sol) = 0.97 +/- 0.02, independently of enzyme loading. Vesicles became very permeable to SOD when membrane bound NaChol concentration exceeded 13.7 mM, in case of total starting lipid concentration of 138 mM diluted to SPC = 19.6 mM. Specifically, we measured a 50% loss of SOD from the vesicles with an aggregate-associated molar detergent ratio NaChol/SPC approximately 0.7, which is near the saturation but well below the solubilisation limit. Calcein efflux from such vesicles was compared with SPC/NaChol/SOD mixed aggregates. Our results should contribute to the future design of vesicle mediated transdermal delivery of antioxidant enzymes.     

Physicochemical properties of liposomes incorporating hydrochlorothiazide and chlorothiazide

In an attempt to study the effect of hydrophobic drugs on liposome properties, multilamellar liposomes (MLV) consisting of phosphatidylcholine (PC) and incorporating chlorothiazide (CT) or hydrochlorothiazide (HCT), were prepared and characterized. Liposome size, surface charge, stability (in buffer, plasma and sodium cholate) and calcium-induced aggregation were studied for drug-incorporating liposomes and empty liposomes for comparison. Results show that drug incorporation affects liposome size, z-potential and stability in presence of buffer and plasma proteins. Indeed, drug-incorporating liposomes are slightly larger and have a negative surface charge, which increases with the amount of drug incorporated in the lipid membrane. The membrane integrity of drug incorporating liposomes (in absence and presence of plasma proteins) is significantly higher when compared with that of empty liposomes (for both drugs studied). On the contrary, vesicle membrane integrity in presence of sodium cholate and calcium induced vesicle aggregation, are not affected by drug incorporation. Leakage of thiazides from liposomes was demonstrated to be induced by dilution. Low amounts of thiazides (around 10-15%) are released when lipid concentration is over 0.1 mM, while further dilution increased drug leakage exponentially. Concluding, results demonstrate that the presence of HCT or CT in liposome membranes has a significant effect on main vesicle properties, which are known to influence vesicle targeting ability. Thereby, it is very interesting to continue studies in this respect, especially with more lipophilic drugs.     

Solubilization and pharmacokinetic behaviors of sodium cholate/lecithin-mixed micelles containing cyclosporine A

The purpose of this study was to investigate the solubilization capacity of sodium cholate/lecithin-mixed micelles and to evaluate the potential of mixed micelles as a carrier of cyclosporine A for intravenous infusion. The mixed micelles were prepared by coprecipitation technique. The formulation components and preparation procedures, which may affect the solubilization of cyclosporine A, were studied. The dilution stability of cyclosporine A-containing mixed micelles was investigated. Pharmacokinetic behaviors of mixed micelles in rabbits after intravenous infusion were compared with Sandimmun. Results showed the strategies to increase the solubility of cyclosporine A include lowering the molar ratio of sodium cholate to lecithin, increasing the concentration of lecithin, and reducing the ionic strength of the dispersion medium and temperature. The largest solubility was found to be 5.42 +/- 0.16 mg/ml. The leakage of mixed micelles in 5% glucose (5.84%) was much less than that in saline solution (36.7%). The relative bioavailability of mixed micelles versus Sandimmun was 112 +/- 20%, and statistical analysis demonstrated both preparations were bioequivalent. Sodium cholate/lecithin-mixed micelles are promising carriers in the intravenous delivery of cyclosporine A, considering their capability of large-scale production and low-toxic property.     

Preparation and Characterization of Ethosomes for Topical delivery of Aceclofenac

The aim of present study was to prepare and characterized ethosomes of aceclofenac which may deliver the drug to targeted site more efficiently than marketed gel preparation and also overcome the problems related with oral administration of drug. The formulations were prepared with varying the quantity of ethanol 10-50% (v/v), lecithin 1-4% (w/v), propylene glycol 5-20% (v/v) and evaluated for their vesicle size, shape and surface morphology, entrapment efficiency and in vitro drug permeation study. Ethosomes of average size of 1.112 μm with a spherical shape bearing smooth surface were observed by transmission electron microscopy and surface electron microscopy. The maximum entrapment of ethosomes was 91.06±0.79%. Cumulative amount of drug permeated through the biological membrane was found to be in the range of 0.26±0.014 to 0.49±0.032 mg/cm(2). Stability profile of prepared system was assessed for 45 days and the results revealed that very less degradation of drug was observed during storage condition.