Article

Formulation and evaluation of naproxen proniosomal gel for the treatment of inflammatory and degenerative disorders of the musculoskeletal system

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Abstract

Non-ionic surfactant based Proniosome Gels of naproxen sodium, an cox II inhibitor, were prepared by coacervation phase separation method. The prepared systems were characterised for encapsulation efficiency, shape, size and in vitro drug release. Stability study was carried out to investigate the leaching of drug from the proniosomal system during storage. The results showed that naproxen in all the formulations was successfully entrapped and a substantial change in release rate and an alteration in the encapsulation efficiency of naproxen from proniosomes were observed upon varying the type of surfactant and cholesterol content. The encapsulation efficiency of proniosomes prepared with Span 40:60 was superior to that prepared with all Span prepration . A preparation with Span 40: 60, cholesterol and lecithin gave maximum encapsulation efficiency (84.61%) and release results (Q24h= 81%) as compared to other compositions. Proniosomal formulations showed fairly high retention of naproxen inside the vesicles at refrigerated temperature (4-8oC) up to 1 month. Keywords: Naproxen, proniosomes, Niosomes, encapsulation efficiency, drug delivery.

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... The appearance of each formulation was checked for its color, consistency, and fluidity by spreading a thin layer of gel on a glass slide and placing the coverslip on it. [23,24] pH Determination Digital pH meter was used to determine the pH of proniosomal gel. The pH meter was calibrated before use with buffered solution pH 4.0, 7.0, 10.0. ...
... The measurement of pH of every formulation was replicated two times, and then the average value was calculated. [23,24] ...
... The particle sizes of vesicles were measured using a calibrated ocular and stage micrometer built-in optical microscope. [23][24] ...
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Proniosomal gel formulations of miconazole nitrate (MCZ) were prepared by using combinations of different grades of (non-ionic surfactant) span, cholesterol, and lecithin by coacervation phase separation method. Developed 10 proniosomal gel formulations were characterized for particle size, shape, % entrapment efficiency, drug content, in vitro drug permeation, scanning electron microscopy (SEM), DSC, stability study. The fourier transform infrared spectroscopy (FTIR) studies confirmed the compatibility of the drug with excipients. The results showed that all the formulations were pale yellow to pale brown in color, pH was is in the range of 5.60 to 7.20, and encapsulation efficiency was found is in the range of 83 to 91.25% and particle size in between 5.81 ± 0.2 to 07.52 ± 0.07. Among the ten formulations MF2, MF3, MF5, MF6, and MF8 showed maximum drug release in a controlled manner at 12 hours of study and developed into carbopol proniosomal topical gel and evaluated for ex-vivo drug permeation. Formulationoptimized formulation C5MF8 showed higher drug permeation 74.19 ± 0.16% at 12 hr. with a flux valueof 6.829 ± 0.12 μg/cm2 /hr. The permeability coefficient of 0.341 ±0.08 cm2 /hrs., higher correlation coefficient R2 0.9944 for zero-order drug release kinetic model, and follows zero-order release kinetics. Among the 5 formulations, optimized carbopol proniosomal topical gel formulation C5MF8 drug release and in-vitro antifungal activity was compared with marketed formulation cream.C5MF8 showed sustain drug release and zone of inhibition value was very near to marketed preparation. Hence it was concluded that developed carbopol proniosomal topical gel had the potential to act as a controlled release drug carrier,which sustains the drug release for many hours and exhibit good antifungal activity
... Moreover, the study of Nap release from Lid-free hydrogels revealed that the release rate constant was the highest when the drug was released from the formulation with the lowest carrier concentration and the lowest hydrogel viscosity [23], and this was consistent with the results obtained in this work. The kinetics of the Nap release from different hydrogels or transdermal systems was also analyzed by employing zero-and first-order equations as well as Higuchi and Korsmeyer-Peppas models [44,45]. It was found that the best model, depending on the formulation, was Korsmeyer-Peppas or zero-order, although the Higuchi model and the first-order equations also had very high coefficient R 2 values. ...
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Sodium hyaluronate (HA) is a natural polysaccharide. This biopolymer occurs in many tissues of living organisms. The regenerating, nourishing, and moisturizing properties as well as the rheological properties of HA enable its application in the pharmaceutical industry as a carrier of medicinal substances. The aim of this work was to assess the release of naproxen sodium (Nap) in the presence of lidocaine hydrochloride (Lid) from the biopolymer-based hydrogels and to determine the respective kinetic parameters of this process. The possible interaction between the HA polysaccharide carrier and the selected drugs was also investigated. Three hydrogels containing Nap and Lid with different concentrations of the biopolymer were prepared. The release of Nap was studied by employing USP apparatus 5. The infrared study and differential scanning calorimetry analysis of physical mixtures and dried formulations were performed. The highest amount of Nap was released from the formulation with the lowest concentration of the biopolymer. The most representative kinetic model that described the dissolution of Nap was obtained through the Korsmeyer–Peppas equation. The release rate constants were in the range of 1.0 ± 0.1 × 10−2 min−n–1.7 ± 0.1 × 10−2 min−n. Lid did not influence the dissolution of Nap from the formulations tested; however, in the desiccated samples of assessed formulations, the interaction between the polysaccharide and both drugs was observed.
... This indicate that the drug was effectively encapsulated for each composition, with such a significant difference in the release profile. The encapsulation efficiency of naproxen in the form of proniosomes was altered by various kinds of surfactants and cholesterol content [55]. ...
... But in the long term use of naproxen in auto immune diseases, it may cause gastric bleeding and can increase the risk of fatal heart attack or stroke. To overcome these side effects of naproxen, there is a need to employ novel drug delivery system like niosomes [11,12]. ...
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The objective of the present research was to prepare and characterize naproxen loaded niosomes by ether injection method. A total of sixteen formulations were prepared by ether injection method by varying the type and concentration of surfactant. All the formulations were evaluated for drug content, entrapment efficiency, loading capacity and drug release profiles. Based on evaluation parameters, formulation E14 prepared by ether injection method showed entrapment efficiency of 95.86%, drug content of 94.9%, zeta potential value of -31.9 mV, suggesting its higher stability and particle diameter of about 393.9 nm. In-vitro release studies also showed that of all the formulations, E14 released about 88.9% by the end of 12 hours, showing a sustained release pattern with high amount of drug release when compared to the other formulations. Drug release kinetic studies of optimized formulation (E14) followed zero order release with R2 value of 0.987 and showed super case 2 transport mechanism. Based on the results, tween 80 with 1:1 ratio of drug to surfactant was considered as the best formulation for the preparation of naproxen loaded niosomes by ether injection method.
... Then the aqueous phase (phosphate buffer saline pH 7.4)was added and warmed on a water bath till a clear solution was formed which was converted intoProniosomal gel on cooling. The gel thus obtained was preserved within the same glass bottle in dark conditions for characterization.[14] Method of preparation of proniosome www.wjpr.netVol ...
... Niosomes are non ionic surfactant based vesicular systems in combination with lipid or other polymers. The amphiphilic property of surfactant allows entrapment of both hydrophilic and lipophilic drugs and controls the release of drug as observed in naproxen loaded niosomes [55]. These are stable, biocompatible, non immunogenic and economical system compared to other vesicular system. ...
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Rheumatoid arthritis (RA) is an autoimmune disorder distinct with series of complex change with unknown genesis. Constant effort has been made to treat RA through varied form of bioactives involving drugs, biologics, enzymes, genetic and hormones. Thus advancement in therapy involved introduction of targeted approaches and formulation of novel carters for efficient therapy. Current review is an attempt to contemplate RA in terms of pathogenesis, causative factors, targeted approaches, delivery of drugs through targeted ligands, novel carters as vesicular, particulate, self assembled, cellular and ceramic systems. Various polymeric components, drugs, biological molecules could be tailored directly or indirectly to target cells, bone site (hydoxyappatite), and macrophage cells to treat RA. The additional benefit of cellular carriers like erythrocytes and lymphocytes cells warrant likelihoods for delivery of peptides and recombinant proteins effectively.
... Proniosomes were prepared by a coacervation phase separation method (Gadekar et al., 2013;Ramkanth et al., 2014;Rajabalaya et al., 2015). Precisely weighed amounts of surfactant, soya lecithin, cholesterol, and drug were taken in a clean and dry wide mouthed glass vial of 5.0 ml capacity and absolute ethanol (0.25 ml) was added to it. ...
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The preparation of lipid vesicles using simple coacervation is described in detail. The optimal coacervation conditions for the formation of lipid vesicles by the triangular phase diagram of the lipid-alcohol-water system were examined. Four different alcohols (methanol, ethanol, n-propanol, and 2-propanol) were used as a lipid solvent, and deionized, distilled water was used as a poor solvent for the lipids. The lamellarity and size homogeneity of the resulting lipid vesicles were observed by freeze-fracture electron microscopy and scanning electron microscopy, respectively, using a specific fixation technique with malachite green. The majority of vesicles formed by methanol as a lipid solvent appeared to be large and unilamellar, ranging from 100 to 1000 nm in diameter. However, when the vesicles were prepared using ethanol, concentric lamellae of multilamellar vesicles were recognizable. On the other hand, the use of propanol resulted in lipid vesicles that were homogeneous and unilamellar.
Article
A critical analysis of (trans) dermal delivery of substances encapsulated within liposomes and niosomes is presented. Topical liposomes or niosomes may serve as solubilization matrix, as a local depot for sustained release of dermally active compounds, as penetration enhancers, or as rate-limiting membrane barrier for the modulation of systemic absorption of drugs. The mechanism(s) of vesicle-skin interaction and drug delivery are being extensively investigated using radioactive- or fluorescence-labeled marker molecules and drugs, and various electron and (laser) light microscopic visualization techniques, and different models describing the interaction with and fate of vesicles in the skin have been proposed. With the current experimental data base on hand, most investigators agree that direct contact between vesicles and skin is essential for efficient delivery, although phospholipids per se apparently do not penetrate into deeper skin layers. Investigators have mostly focused on dermal corticosteroid liposome products. However, localized effects of liposome-associated proteins such as superoxide dismutase, tissue growth factors and interferons appear also to be enhanced. The delivery of liposome-encapsulated proteins and enzymes into deeper skin layers has been reported, although the mechanism of delivery remains to be elucidated. An objective assessment of the performance of topical liposome formulations vs. conventional dosage forms is frequently obscured by investigators comparing equal concentrations, rather than equivalent thermodynamic activities of their respective formulations. We conclude that liposomes and niosomes may become a useful dosage form for a variety of dermally active compounds, specifically due to their ability to modulate drug transfer and serve as nontoxic penetration enhancers.
Article
The skin permeation and partitioning of a fluorinated quinolone antibacterial agent, enoxacin, in liposomes and niosomes, after topical application, were elucidated in the present study. In vitro percutaneous absorption experiments were performed on nude mouse skin with Franz diffusion cells. The influence of vesicles on the physicochemical property and stability of the formulations were measured. The enhanced delivery across the skin of liposome and niosome encapsulated enoxacin had been observed after selecting the appropriate formulations. The optimized formulations could also reserve a large amount of enoxacin in the skin. A significant relationship between skin permeation and the cumulative amount of enoxacin in the skin was observed. Both permeation enhancer effect and direct vesicle fusion with stratum corneum may contribute to the permeation of enoxacin across skin. Formulation with niosomes demonstrated a higher stability after 48 h incubation compared to liposomes. The inclusion of cholesterol improved the stability of enoxacin liposomes according to the results from encapsulation and turbidity. However, adding negative charges reduced the stability of niosomes. The ability of liposomes and niosomes to modulate drug delivery without significant toxicity makes the two vesicles useful to formulate topical enoxacin.
Article
Considerable interest in using the transdermal route for drug administration has strengthened the need for investigations of vehicle effects. The influence of ethanol on the in vitro transport behaviour of saturated oestradiol (OE) solutions through excised human skin and model membranes (silastic, human skin-silastic sandwich and snake skin) was investigated over 0–90% w/w ethanol/water vehicle compositions. Human skin showed a maximum flux of OE (1.45 ± 0.39 μ cm-2 h-1) at ethanol vehicle contents between 40 and 60% w/w. Silastic membranes were used to help elucidate the mechanisms of ethanol as an enhancer. Partition coefficients and uptake of OE by stratum corneum and silastic membranes from the co-solvent systems were determined and the results suggested that the enhanced permeation of OE from vehicles with ethanol concentrations up to 60% w/w was partially related to increased drug solubility in the stratum corneum. The other part was related to ethanol effects on stratum corneum components. The decrease of OE flux from vehicles with higher ethanol concentrations was due to ethanol dehydration effects on the stratum corneum. This was confirmed by measuring the uptake of ethanol and water from different concentrations of ethanol; increasing ethanol concentration in the donor produced a significant decrease in the stratum corneum water content. Also, when the skin hydration was controlled using the skin-silastic sandwich model, the OE flux did not significantly decrease at high ethanol concentration. Ethanol actions were further investigated by measuring the permeation rate of OE through a model animal membrane, shed snake skin. Different results were obtained than for human skin and silastic membrane. The maximum flux of OE through dorsal snake skin appeared at higher ethanol vehicle concentration (80% w/w) when compared with human skin. Ventral snake skin showed increasing OE flux up to 40% w/w ethanol which remained essentially constant up to 90% ethanol. The results obtained with snake skin were attributed to the lower water content of this membrane.
Article
The aim of this study was to investigate an influence of different types of membrane additives including negative charge (dicetylphosphate, DCP), positive charge (stearylamine, STR) and non-ionic molecule (cholesteryl poly-24-oxyethylene ether, SC24) on the physicochemical properties of drug-free and drug-loaded niosomes. Salicylic acid having different proportions of ionized and unionized species at different pH was selected as a model drug. The niosomes were composed of 1:1 mole ratio of Span 60: cholesterol as vesicle forming agents. The results show that incorporation of salicylic acid to the niosomes did not affect zeta potential values; however, addition of the membrane additives changed the zeta potential depending on the type of the additives. Transmission electron microscopy revealed that niosomes had unilamellar structure. The particle sizes of all developed niosomes were between 217 to 360 nm. The entrapment efficiency (%E.E.) of all salicylic acid niosomes at pH 3 was higher than that of niosomes at pH 5, indicating that salicylic acid in unionized form was preferably incorporated in niosomes. Furthermore, the positively charged niosomes showed the highest %E.E. of salicylic acid owing to electrostatic attraction between STR and salicylic acid. After 3 months of storage at 4 degrees C, the particle size of the niosomes remained in the nanosize range except for DCP salicylic acid niosomes at pH 3 whose size increased due to an instability of DCP at low pH. In addition, all niosomes showed no leakage of the salicylic acid after 3 months of storage indicating the good stability.
Article
Vinpocetine (Vin) existing oral formulations suffer poor bioavailability (∼7%) since Vin undergoes a marked first-pass effect (∼75%) and its absorption is dissolution rate-limited. In this study, a novel sustained release proniosomal system was designed using sugar esters (SEs) as non-ionic surfactants in which proniosomes were converted to niosomes upon skin water hydration following topical application under occlusive conditions. Different in vitro aspects (encapsulation efficiency, vesicle size and shape, effect of occlusion, in vitro release, skin permeation and stability) were studied leading to an optimized formula that was assessed clinically for transdermal pharmacokinetics and skin irritation. All formulae exhibited high entrapment efficiencies, regardless of the surfactant HLB. Vesicle size analysis showed that all vesicles were in the range from 0.63 μm to 2.52 μm which favored efficient transdermal delivery. The extent of drug permeation through the skin from the optimized formula--containing laurate SE with shorter fatty acid chain length and high HLB--was quite high (91%) after 48 h under occlusive conditions. The extent of absorption of Vin from proniosomes was larger when compared to the oral tablet with a relative bioavailability (F(rel)) of 206%. Histopathological evaluation revealed only moderate skin irritation when using SEs compared to skin inflammation when using Tween 80. Sugar esters proniosomes may be a promising carrier for vinpocetine, especially due to their simple scaling up and their ability to control drug release.
Article
The objectives of this research were to prepare ribavirin niosomes and evaluate the influence of niosomal encapsulation on drug liver targeting in rats. Ribavirin niosomes were prepared by the thin film hydration method using span 60, cholesterol, and dicetyl phosphate in molar ratios of (1:1:0), (4:2:0), (1:1:0.1), and (4:2:1). The prepared niosomes were characterized in vitro for vesicle size, drug entrapment, drug release profiles, and vesicular stability at refrigerator temperature. The results indicated that niosomes of the molar ratio (4:2:1) had a significantly (p < 0.05) higher entrapment percentage of ribavirin than the other molar ratios, moreover, they revealed sustained release characteristics as well as longer release pattern than other niosomal formulations. Accordingly, niosomes of molar ratio (4:2:1) was selected for in vivo liver targeting study. Separately, niosomal ribavirin dispersion and free ribavirin solution were administered as a single dose of 30 mg/kg by intraperitoneal injection into two groups of rats to compare the liver ribavirin concentration. The obtained results show that the niosomal formulation significantly increased ribavirin liver concentration (6-fold) in comparison with ribavirin-free solution. Based on the previous results, the use of niosomes as a drug delivery system for ribavirin has significant liver targeting properties, this is expected to improve the efficacy of low doses of ribavirin and minimize its toxic side-effects at higher doses.
Article
Niosomes have been reported as a possible approach to improve the low skin penetration and bioavailability characteristics shown by conventional topical vehicle for minoxidil. Niosomes formed from polyoxyethylene alkyl ethers (Brij) or sorbitan monoesters (Span) with cholesterol molar ratios of 0, 1 and 1.5 were prepared with varying drug amount 20-50mg using thin film-hydration method. The prepared systems were characterized for entrapment efficiency, particle size, zeta potential and stability. Skin permeation studies were performed using static vertical diffusion Franz cells and hairless mouse skin treated with either niosomes, control minoxidil solution (propylene glycol-water-ethanol at 20:30:50, v/v/v) or a leading topical minoxidil commercial formulation (Minoxyl). The results showed that the type of surfactant, cholesterol and incorporated amount of drug altered the entrapment efficiency of niosomes. Higher entrapment efficiency was obtained with the niosomes prepared from Span 60 and cholesterol at 1:1 molar ratio using 25mg drug. Niosomal formulations have shown a fairly high retention of minoxidil inside the vesicles (80%) at refrigerated temperature up to a period of 3 months. It was observed that both dialyzed and non-dialyzed niosomal formulations (1.03+/-0.18 to 19.41+/-4.04%) enhanced the percentage of dose accumulated in the skin compared to commercial and control formulations (0.11+/-0.03 to 0.48+/-0.17%) except dialyzed Span 60 niosomes. The greatest skin accumulation was always obtained with non-dialyzed vesicular formulations. Our results suggest that these niosomal formulations could constitute a promising approach for the topical delivery of minoxidil in hair loss treatment.
Article
The oral route is most preferred for chronic drug therapy. Poor oral bioavailability has the consequences of more variable and poorly controlled plasma concentrations and drug effects, in addition to possibly increased product cost. In this review, the most common causes of low oral bioavailability are categorized, and formulation strategies to improve bioavailability are summarized. Various methods that can be used to help identify the cause of low bioavailability are discussed. The focus of this article is on poor membrane permeation and presystemic degradation problems; solubility/dissolution rate problems are discussed only briefly. Poor membrane permeation and presystemic degradation problems are typically encountered in the efforts to develop oral proteins, peptides, and peptide mimics. Formulation strategies reviewed include the use of metabolism inhibitors, membrane permeation enhancers, ion pairing and complexation, and particulate carriers. Also reviewed are lipid and surfactant formulations, which have been shown to increase bioavailability by various mechanisms and which are only beginning to be understood and optimized.
Article
A proniosome based transdermal drug delivery system of levonorgestrel (LN) was developed and extensively characterized both in vitro and in vivo. The proniosomal structure was liquid crystalline-compact niosomes hybrid which could be converted into niosomes upon hydration. The system was evaluated in vitro for drug loading, rate of hydration (spontaneity), vesicle size, polydispersity, entrapment efficiency and drug diffusion across rat skin. The effect of composition of formulation, amount of drug, type of Spans, alcohols and sonication time on transdermal permeation profile was observed. The stability studies were performed at 4 degrees C and at room temperature. The biological assay for progestational activity included endometrial assay and inhibition with the formation of corpora lutea. The study demonstrated the utility of proniosomal transdermal patch bearing levonorgestrel for effective contraception.
Article
We describe an early prototype of a pulsatile delivery system for drug containing vesicles. Nonionic surfactant vesicles (niosomes) of average diameter 4-30 microm are extruded from glass capillaries (exit diameter, 5-10 microm), using air pressures of 0.5-5 p.s.i. The formulation of the vesicles is vital. Extrusions were affected by the size, shape, and membrane composition of the niosomes used. Spherical or polyhedral niosomes, formed by polyoxyethylene alkyl ethers with and without cholesterol, respectively, with diameters larger than the exit diameter of the capillary do not retain their membrane integrity on extrusion and were sheared to form new ultrastructures. The expulsion of single or groups of intact polystyrene microspheres or tetradecyl-beta-D-maltoside niosomes with sizes smaller than the exit diameter can be achieved readily. The stepwise release profile of luteinizing hormone releasing hormone (LHRH) obtained after pulsatile expulsion of groups of niosomes entrapping LHRH indicates the feasibility of this system for pulsatile delivery of vesicles, although it requires miniaturization.
Article
In this study soya-lecithin aggregates, prepared by a technique using compressed gas, are used to formulate new dermal preparations. Ketoprofen (KP), a nonsteroidal anti-inflammatory drug (NSAID) is included as a model drug. The technique offers the possibility of incorporating auxiliary agents, such as penetration enhancers, anti-irritants and moisturisers together with the drug in one process. Apparent partition coefficients for n-octanol-phosphate buffer were determined for each of the lecithin aggregates. In general, soya-lecithin improves the partition of KP into n-octanol. The resulting products were included in widely used hydrophilic and hydrophobic vehicles. After 24 h, the cumulative amount of drug released through an artificial membrane was higher from the hydrophilic gels (2.6-4.3 mg) and the hydrophobic creams (0.23-0.392 mg) than from the control preparations (control hydrogel: 1.3 mg; control hydrophobic cream: 0.141 mg). However, the cumulative amount released from the hydrophobic vehicles was generally lower than from the hydrophilic matrices. Cumulative amounts such as those released from the hydrophilic preparations can also be achieved using supersaturated formulations based solely on the drug-loaded lecithin aggregates and a suitable oily component (4.07 mg). Results from the diffusion studies using artificial membranes were confirmed by permeation studies using excised rat skin. The improvement in skin permeation is related to both the solubilising effect of the lecithin matrix and the penetration enhancing effect of lecithin itself. The novel soya-lecithin aggregates are promising candidates for new drug delivery systems in dermatology and cosmetology. Lecithin aggregates loaded with drugs are multifunctional carriers that also act as penetration enhancers.
Article
Niosomes are vesicles formed by self-assembly of non-ionic surfactants. In this investigation, the effects of processing variables, particularly temperature and sonication, on the physical characteristics and phase transitional behaviour of two niosomal systems based on a hexadecyl diglycerol ether (C(16)G(2)) have been studied. Systems containing C(16)G(2), cholesterol and poly-24-oxyethylene cholesteryl ether (Solulan C24) in the molar ratios 91:0:9 and 49:49:2 were prepared by aqueous dispersion of films, followed by examination of 5(6)-carboxyfluorescein entrapment, particle size and morphology. The thermal behaviour was examined using high sensitivity differential scanning calorimetry (HSDSC) and hot stage microscopy, while the effects of sonication were studied in terms of size and morphology, both immediately after preparation and on storing for 1 h at room temperature and 60 degrees C. Polyhedral niosomes were formed from systems containing C(16)G(2) and Solulan C24 alone, while cholesterol-containing systems formed spherical vesicles mixed with tubular structures; the polyhedral systems were found to have a larger particle size and higher CF entrapment efficiency. HSDSC studies showed the polyhedral systems to exhibit an endotherm at 45.4 degrees C and a corresponding exotherm at 39.1 degrees C on cooling which were ascribed to a membrane phase transition; no equivalent transition was observed for the cholesterol containing systems. Hot stage microscopy showed the polyhedral vesicles to convert to spherical structures at approximately 48 degrees C, while on cooling the spherical vesicles split into smaller structures and reverted to the polyhedral shape at approximately 49 degrees C. Sonication resulted in the polyhedral vesicles forming spherical structures which underwent a particle size increase on storage at room temperature but not at 60 degrees C. The study suggests that the polyhedral vesicles undergo a reversible transition to spherical vesicles on heating or sonication and that this morphological change may be associated with a membrane phase transition.
Article
To prepare niosomes which have high encapsulation capacity for soluble drugs, starting from Span 60 and cholesterol, an improved method, evaporation-sonication method, was proposed. The corresponding niosomes show a good stability at least 40 days. Colchicine was chosen as a model drug for examining the capsulation capacity of these niosomes. To obtain the highest encapsulation efficiency, several factors including the structure of surfactant, level of lipid, content of drug and cholesterol were investigated and optimized. The inner cause was also discussed. The results indicate that the Span 60 is the most ideal surfactant among four kinds of Span. Furthermore, the release studies of colchicine and 5-fluorouracil (5-FU) in vitro from niosomes exhibited a prolonged release profile as studied over a period of 24 h. The results demonstrated that niosomes prepared in this way not only have high encapsulation capacity but also is expected that side effects of drugs may be reduced. It still suggests that this method may be used extensively in the field of encapsulation soluble drugs.
Article
The natural function of the skin is to protect the body for unwanted influences from the environment. The main barrier of the skin is located in the outermost layer of the skin, the stratum corneum. Since the lipids regions in the stratum corneum form the only continuous structure, substances applied onto the skin always have to pass these regions. Therefore, in the first part of this paper, the barrier function has been explained, focusing on the lipid composition and organisation. The major obstacle for topical drug delivery is the low diffusion rate of drugs across the stratum corneum. Several methods have been assessed to increase the permeation rate of drugs temporarily. One of the approaches is the application of drugs in formulations containing vesicles. In order to unravel the mechanisms involved in increasing the drug transport across the skin, information on the effect of vesicles on drug permeation rate, the permeation pathway and perturbations of the skin ultrastructure is of importance. In the second part of this paper, the possible interactions between vesicles and skin are described, focusing on differences between the effects of gel-state, liquid-state, and elastic vesicles.
Article
Liposomes have been extensively studied and suggested as a vehicle for topical drug delivery systems. However, the mechanism by which liposomes deliver drugs into intact skin is not fully understood. In the present study, we have tried to understand the mechanism of transport of hydrophilic drugs into the skin using liposomes. The effect of separation of the non-entrapped, hydrophilic fluorescent compound, carboxyfluorescein (CF), from liposomally entrapped CF was investigated by measuring the penetration of CF across human skin under non-occlusive conditions in vitro using Franz diffusion cells. The fluorescent dye, CF, was incorporated into the liposomes and applied onto the skin. After a 6 and 12h incubation period, the amount of CF in the epidermal membrane and the full thickness skin was determined by fluorescence spectroscopy or by confocal laser scanning microscopy (CLSM). The liposomal formulation containing CF both inside and outside the vesicles showed statistically enhanced penetration of CF into the human stratum corneum (SC) as compared to the formulations containing CF only outside of the liposomes and CF in Tris buffer. The CLSM results revealed that the formulation in which CF was present outside the liposomes showed bright fluorescence intensity in the SC and very weak fluorescence in the viable epidermis. However, the CF in Tris buffer failed to show any fluorescence in the viable epidermis. The results indicated that phospholipid vesicles not only carry the entrapped hydrophilic substance, but also the non-entrapped hydrophilic substance into the SC and possibly into the deeper layers of the skin.
Article
The main aim of pharmacotherapeutics is the attainment of effective drug concentration at the intended site of action for a sufficient period of time to elicit a response. Poor bioavailability of drugs from ocular dosage form is mainly due to the tear production, non-productive absorption, transient residence time, and impermeability of corneal epithelium. Though the topical and localized application are still an acceptable and preferred way to achieve therapeutic level of drugs used to treat ocular disorders but the primitive ophthalmic solution, suspension, and ointment dosage form are no longer sufficient to combat various ocular diseases. This article reviews the constraints with conventional ocular therapy and explores various novel approaches, in general, to improve ocular bioavailability of the drugs, advantages of vesicular approach over these and the future challenges to render the vesicular system more effective.
Article
The main objective of the present work was to compare the dermal delivery of minoxidil (Mx), a lipophilic drug from ethosomes versus classic liposomes, containing different cholesterol (CHOL) concentrations. All the systems were characterized for shape, lamellarity, particle size and entrapment efficiency percentage (EE), by transmission electron microscopy (TEM), confocal laser scanning microscopy (CLSM), laser diffraction and ultracentrifugation or dialysis methods, respectively. Multilamellar vesicles (MLVs) were obtained and one to six lamellae were visualized by CLSM. The presence of ethanol in the formulations affects the particle size in terms of reducing this parameter. In addition, it was possible to appreciate the influence of CHOL on the vesicle size, because it was increased, as CHOL concentration was higher. When the EE was determined by two different methods (ultracentrifugation and dialysis methods), a clear losing of entrapped drug by the ultracentrifugation method was observed, because the strong energy transmitted to the samples disrupted vesicles. Vesicles were non-occlusively applied on rat skin and the permeation pattern of the different systems, depth into the skin and the main permeation pathway were studied by using beta-carotene as a fluorescent probe. CLSM studies showed that ethosomal systems were much more efficient at delivering the fluorescent substance into the skin in terms of quantity and depth, than either liposomes or hydroalcoholic solutions.
Article
The mechanical characteristics of non-ionic bilayer membranes composed of sorbitan monostearate, cholesterol and poly-24-oxyethylene cholesteryl were studied by measuring the modulus of surface elasticity (mu), a measure of membrane strength, as a function of cholesterol content and temperature. The modulus of surface elasticity increased slowly with increasing cholesterol concentration, with a sharp increase around 40 mol% cholesterol (on average an increment of 0.43x10(6) Nm(-2) per molar percentage), and displayed a maximum of 6.5x10(6) Nm(-2) around 47.5 mol% cholesterol. Further cholesterol resulted in a decrease in mu. Generally the interaction of cholesterol with sorbitan monostearate should increase the rigidity of the membrane. However, the latter effect may be due to the formation of cholesterol clusters at high cholesterol content where excess amounts of cholesterol cannot interact with the sorbitan monostearate, and deposits on the bilayers compromising their uniformity, strength and permeability. This behavior was evident when measurements were carried out above and below 25 degrees C.
Article
Feasibility of developing a transdermal drug delivery of fluoxetine has been investigated. Permeation studies of fluoxetine across human cadaver skin were carried out using Franz diffusion cells. The receptor phase consisted of pH 7.4 phosphate buffer maintained at 37 degrees C. Permeation enhancement of fluoxetine, either in the salt or base form, was achieved using various enhancers like azone, SR-38, and ethanol. Various O/W microemulsion systems of fluoxetine were developed to study their effect on the skin permeation of fluoxetine. The results indicated that ethanol at 65% vol/vol was able to increase the permeation of fluoxetine the most, while microemulsion systems showed decrease in the permeation of fluoxetine. The permeation of fluoxetine obtained using a 65% vol/vol ethanolic solution was found to be sufficient to deliver the required dose (20-80 mg) from a patch of feasible size. The results seem promising for developing a transdermal drug delivery system of fluoxetine.
Article
Despite intensive research, the mechanisms by which vesicular systems deliver drugs into intact skin are not yet fully understood. In the current study, possible mechanisms by which deformable liposomes and ethosomes improve skin delivery of ketotifen under non-occlusive conditions were investigated. In vitro permeation and skin deposition behavior of deformable liposomes and ethosomes, having ketotifen both inside and outside the vesicles (no separation of free ketotifen), having ketotifen only inside the vesicles (free ketotifen separated) and having ketotifen only outside the vesicles (ketotifen solution added to empty vesicles), was studied using rabbit pinna skin. Results suggested that both the penetration enhancing effect and the intact vesicle permeation into the stratum corneum might play a role in improving skin delivery of drugs by deformable liposomes, under non-occlusive conditions, and that the penetration enhancing effect was of greater importance in case of ketotifen. Regarding ethosomes, results indicated that ketotifen should be incorporated in ethosomal vesicles for optimum skin delivery. Ethosomes were not able to improve skin delivery of non-entrapped ketotifen.
Article
Sucrose esters (SE) are surfactants with potential pharmaceutical applications because of their low toxicity, biocompatibility, and excellent biodegradability. The objective of the study was to investigate SE as alternative surfactants in stabilizing emulsions for the preparation of protein-loaded microparticles. To achieve this goal, using bovine serum albumin as model protein and 75/25 poly(d,l-lactide-co-glycolide) as polymer carrier, we have investigated the influence of the following formulation variables on particle characteristics: (1) SE concentration from 0.01% to 1% (wt/vol), (2) hydrophile-lipophile balance (HLB) value of SE from 6 to 15, and (3) the nature of emulsion stabilizer. The formulations were characterized using ATR-FTIR spectroscopy, bicinchoninic acid protein assay, optical microscopy and SDS-PAGE. Results showed that at 0.05% (wt/vol) surfactant concentration, SE with HLB of 6 to 15 provided discrete and spherical microparticles with the highest encapsulation efficiency compared with controls polyvinyl alcohol (PVA) and poloxamer 188. These results may be explained by the difference in critical micelle concentration, diffusion, and partition coefficient among the tested surfactants. HLB values were consistent with SE spectral data. The protein molecular weight was preserved after the encapsulation process. The effective SE concentration was far less (20- to 200-fold) than that is usually required for PVA in microencapsulation of proteins. However, the encapsulation efficiency was relatively lower (approximately 13.5%). These preliminary results suggest that it may be desirable to optimize such formulations in vitro and in vivo for SE to be eventually used as alternative surfactants in the development of microparticulate systems for parenteral delivery of protein and gene medicines.
Article
A Novel approach was developed for the preparation of controlled release proniosome-derived niosomes, using sucrose stearates as non-ionic biocompatible surfactants for the nebulisable delivery of cromolyn sodium. Conventional niosomes were prepared by a reverse phase evaporation method followed by the preparation of proniosomes by spraying the optimized surfactant-lipid mixture of sucrose stearate, cholesterol and stearylamine in 7:3:0.3 molar ratio onto the surface of spray dried lactose powder. Proniosome-derived niosomes were obtained by hydrating proniosomes with 0.9% saline at 50 degrees C and mixing for approximately 2 min. All vesicles were evaluated for their particle size, morphological characteristics, entrapment efficiency, in vitro drug release, nebulisation efficiency and physical stability at 2-8 degrees C. In addition, coating carrier surface with the surfactant-lipid mixture, during preparation of proniosomes, resulted in smaller, free flowing, homogenous and smooth vesicles with high drug entrapment efficiency. Compared to a standard drug solution, a successful retardation of the drug release rate was achieved with the proniosome-derived niosomes, where the t50% value of the release profile was 18.1h compared to 1.8h. Moreover, high nebulisation efficiency percentage and good physical stability were also achieved. The results are very encouraging and offer an alternative approach to minimize the problems associated with conventional niosomes like degradation, sedimentation, aggregation and fusion.
Article
Colloids from an aqueous suspension can cross the skin barrier only through hydrophilic pathways. Various colloids have a different ability to do this by penetrating narrow pores of fixed size in the skin, or the relevant nano-pores in barriers modelling the skin. Such ability is governed by colloid adaptability, which must be high enough to allow penetrant deformation to the size of a pore in such barrier: for a 100 nm colloid trespassing the skin this means at least 5-fold deformation/elongation. (Lipid) Bilayer vesicles are normally more adaptable than the comparably large (lipid coated) fluid droplets. One of the reasons for this, and an essential condition for achieving a high bilayer adaptability and pore penetration, is a high bilayer membrane elasticity. The other reason is the relaxation of changing colloid's volume-to-surface constraint during pore penetration; it stands to reason that such relaxation requires a concurrent, but only transient and local, bilayer permeabilisation. Both these phenomena are reflected in bilayer composition sensitivity, which implies non-linear pressure dependency of the apparent barrier penetrability, for example. Amphipats that acceptably weaken a membrane (surfactants, (co)solvents, such as certain alcohols, etc.) consequently facilitate controlled, local bilayer destabilisation and increase lipid bilayer flexibility. When used in the right quantity, such additives thus lower the energetic expense for elastic bilayer deformation, associated with pore penetration. Another prerequisite for aggregate transport through the skin is the colloid-induced opening of the originally very narrow ( approximately 0.4 nm) gaps between cells in the barrier to pores with diameter above 30 nm. Colloids incapable of enforcing such widening-and simultaneously of self-adapting to the size of 20-30 nm without destruction-are confined to the skin surface. All relatively compact colloids seem to fall in this latter category. This includes mixed lipid micelles, solid (nano)particles, nano-droplets, biphasic vesicles, etc. Such colloids, therefore, merely enter the skin through the rare wide gaps between groups of skin cells near the organ surface. Transdermal drug delivery systems based on corresponding drug formulations, therefore, rely on simple drug diffusion through the skin; the colloid then, at best, can modulate drug transport through the barrier. In contrast, the adaptability-and stability-optimised mixed lipid vesicles (Transfersomes, a trademark of IDEA AG) can trespass much narrower pathways between most cells in the skin; such highly adaptable colloids thus mediate drug transport through the skin. Sufficiently stable ultra-adaptable carriers, therefore, can ensure targeted drug delivery deep below the application site. This has already been shown in numerous preclinical tests and several phase I and phase II clinical studies. Drug delivery by means of highly adaptable drug carriers, moreover, allows highly efficient and well-tolerated drug targeting into the skin proper. Sustained drug release through the skin into systemic blood circulation is another field of ultradeformable drug carrier application.
New insights into skin structure: scratching the surface
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Current status and future potential of transdermal drug delivery
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