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Advances in studies of phospholipids as carriers in skin topical application
Abstract
ObjectiveThis article provides an overview of characteristics of phospholipids, the characteristics and influential factors ofliposome and microemulsion as carriers for skin delivery of drugs, and the latest advances of the phospholipids carriers in transdermaldelivery systems. The perspective is that phospholipids carriers may be capable of a wide range of applications in the transdermaldelivery system.
... An active topical substance can penetrate the skin through three pathways: intracellular, intercellular and transfollicular pathways [67]. Liposomes penetrate the skin as an intracellular delivery system and deposit the drugs into the outer layer of the skin, providing prolonged release of the drug [68]. Moreover, they cover the wound and maintain a moist environment at the wound's surface, promoting healing [69]. ...
... The amphiphilic property of liposomes helps them to encapsulate both hydrosoluble and liposoluble drugs. Liposomal encapsulation also enhances the solubility and transdermal penetration for some hard-to-dissolve pharmacological agents [68]. Regarding the size of the liposomes, it modifies the capacity of penetration into the skin. ...
Impaired wound healing is an encumbering public health issue that increases the demand for developing new therapies in order to minimize health costs and enhance treatment efficacy. Available conventional therapies are still unable to maximize their potential in penetrating the skin at the target site and accelerating the healing process. Nanotechnology exhibits an excellent opportunity to enrich currently available medical treatments, enhance standard care and manage wounds. It is a promising approach, able to address issues such as the permeability and bioavailability of drugs with reduced stability or low water solubility. This paper focuses on nanosized-lipid-based drug delivery systems, describing their numerous applications in managing skin wounds. We also highlight the relationship between the physicochemical characteristics of nanosized, lipid-based drug delivery systems and their impact on the wound-healing process. Different types of nanosized-lipid-based drug delivery systems, such as vesicular systems and lipid nanoparticles, demonstrated better applicability and enhanced skin penetration in wound healing therapy compared with conventional treatments. Moreover, an improved chemically and physically stable drug delivery system, with increased drug loading capacity and enhanced bioavailability, has been shown in drugs encapsulated in lipid nanoparticles. Their applications in wound care show potential for overcoming impediments, such as the inadequate bioavailability of active agents with low solubility. Future research in nanosized-lipid-based drug delivery systems will allow the achievement of increased bioavailability and better control of drug release, providing the clinician with more effective therapies for wound care.
... Liposome being a nanosized carrier, is an advantage for the topical and transdermal application of molecules, and liposomes can also increase the solubility and diffusion coefficient of molecules in the skin [14,15]. A conventional liposome composes of phospholipids and cholesterol [16]. ...
... The viscosity of all liposome formulations was found to be in the range of 25.54±0.54 to 54±0.32 centipoise (cps). Thus, the pH level and the viscosity of prepared liposome were suitable for topical applications [14]. In case of size, it was found that all the liposome formulations were nanosized, ranging from 200.6 -364.7 nm and in case of PDI, it was in the range of 0.193 -0.484, indicating homogeneous population and narrow size distribution of vesicles [26]. ...
Phenylethyl Resorcinol (PR) is a cosmeceutical skin lightening agent and the purpose of this study was to enhance its stability by using liposomal cream formulation which increases local efficacy and safety. Liposome formulation was prepared by modified ethanol injection method, and it contained soy phosphatidyl choline (SPC), cholesterol (CHO), Tween 80 (TW80) and deoxycholic acid (DA) mixed with 2% PR. The physicochemical properties, skin permeation as well as cellular study were evaluated in order to obtain the optimized formulation. The optimized liposome formulation composed of SPC:TW80:DA (84:16:2.5) and exhibited vesicle size, polydispersity index (PDI) and zeta potential of 286.4±8.04 nm, 0.317±0.03 and-39.20±3.85 mV, respectively. Entrapment efficiency (EE) of liposome formulation was 93.55±0.05%. The vesicle was spherical in shape and showed good physicochemical stability for 4 months. The skin permeation study demonstrated that liposome with a negative charge could result in a high PR skin deposition value of 1732.76±216.24 µg/cm 2 after 24 h. Cellular study showed that liposome formulation could inhibit melanin content in B16 melanoma cells and enhance cell viability in HaCaT keratinocyte cells. The Original Research Article Raknam et al.; JPRI, 32(1): 64-76, 2020; Article no.JPRI.54920 65 optimized PR liposome was incorporated in cream and investigated physicochemical properties, stability and skin permeation. Liposomal PR cream showed a good stability and a superior result than PR cream in skin permeation parameters, as well as in tyrosinase inhibition.
... Stability Studies: Stability studies of prepared ethosomal vesicles were designed on the basis of ICH guidelines. Samples KET were kept at two different temperature i.e. refrigeration temperature (4 ± 2° C) and at room temperature (30 ± 2° C) for 8 weeks [8]. During the study, ethosomal vesicles were observed for physical changes such as colour, appearance, vesicular size and shape. ...
... But further enhancement in concentration of alcohol (> 50%) found to increase the vesicular size and deformity of vesicles. As per literature survey 8,9 in all studies conducted previously with liposomes the vesicles size found to be larger than ethosomes, which definitely proves that, optimum level ethanol may be reduce the vesicle size. ...
Ethosomes are novel vesicular delivery system which has great potential for topical and transdermal delivery of various drugs. Ketoconazole is widely used anti fungal agent used for topical treatment of fungal infection caused by C.albicans. Ethosomes of Ketoconazole (KZ) developed by patented hot-process method with little modifications were evaluated for size, shape and stability. Developed ethosomes were incorporated in to water miscible cream base and evaluated for in-vitro release profile across the membrane. Ethosomes were stable and creams were found to be more efficient in delivery drug across the membrane than a non-ethosomal Ketoconazole cream. The results suggested the potential of ethosomal vesicles for delivering Ketoconzole across the membrane and reiterated its capabilities as a tool for treating topical fungal infections effectively.
... One of the most promising topical vesicular drug delivery systems are liposomes [7][8][9]. In fact, being biocompatible, biodegradable and non-irritant to the skin [10], make liposomes very attractive to be used as carriers for topical therapy. However, to penetrate deeper into the skin it is necessary to incorporate an edge activator into the phospholipid bilayer [7][8][9]. ...
... The vesicles with this composition, known as deformable liposomes (Transfersomes ® ), were developed by Cevc and Blume [11]. Deformable liposomes present higher elasticity than conventional liposomes, allowing their penetration into the pores with 1/5 of their size [10][11][12]. In fact, the extremely high and stress-dependent adaptability permits that deformable liposomes can squeeze between the cells in the stratum corneum, without irreversible disruption, despite their higher diameter than pores in the skin [12]. ...
Deformable Liposomes for the Transdermal Delivery of Piroxicam
Abstract
Objective: Deformable liposomes have been used to improve drugs transdermal delivery. These vesicular systems were employed to deliver piroxicam through the skin as a mean to treat inflammatory diseases and avoid undesired side-effects.
Methods: Deformable liposomes, composed by egg-yolk phosphatidylcholine, sodium cholate and α-tocopherol, were prepared by the thin film hydration method followed by extrusion. Piroxicam was included into the lipid bilayer or in the aqueous phase using inclusion complexes of piroxicam with β-cyclodextrin. After characterization, it was evaluated their in vitro permeation using Franz diffusion cells with polysulfone membranes or pig skin.
Results: The entrapment of piroxicam in the aqueous compartment, through the use of β-cyclodextrin inclusion complexes, enabled higher entrapment efficiency (63.27% more than when entrapped in the lipid bilayer). The optimized deformable liposomes population were homogeneous (PDI < 0.1) in terms of size (108.93 ± 3.74 nm) and presented a spherical shape. Size stability studies demonstrated that the vesicles were stable along two months of storage. In vitro permeation studies using Franz diffusion cells and polysulfone membranes showed that the vesicles own enough deformability to pass through pores smaller than their own size in a percentage ≈ 45%. Furthermore, a constancy of their diameter and morphology was verified after pores passage. In the experiments performed with pig skin, the permeation of the deformable liposomes incorporating piroxicam β-cyclodextrin complexes decrease considerably. After 24 h of diffusion, only 1.1-3.2 % of the initial population reached the liquid receptor as result of the presence of the stratum corneum which is the main barrier of the skin. Nevertheless, the histological studies demonstrated that deformable liposomes were uniformly distributed on the skin structure and thus were able to achieve a percutaneous permeation of their content.
Conclusion: The results support the possibility to use this formulation on the topical treatment of inflammatory conditions.
... Liposomes are vesicular carrier systems, composed of phospholipid layers. These phospholipids have many advantages due to their similarity with skin lipids, like very low toxicity, biodegradability and strong tissue affinity (Liu & Hu, 2007). Drugs can be encapsulated in the aqueous core and/or the membrane of liposomes, which are well tolerated by the skin and also have a strong affinity for the stratum corneum (Santos Maia et al., 2002). ...
... Liposomes enhance the penetration of drugs through the stratum corneum and localize them in the epidermis and dermis. They can penetrate stratum corneum lipid lamellae and fuse with endogenous lipids hence the systemic absorption and side effects can be reduced (Fresta & Puglisi, 1997;Benson, 2005;Liu & Hu, 2007;Zhang et al., 2011). In order to prove that, the ex-vivo permeation experiments were performed using Franz diffusion cells across rat abdominal skin for liposomes, liposome in gels, API in gel and commercial cream. ...
Atopic dermatitis (AD) is a chronic and relapsing skin disease with severe eczematous lesions. Long-term topical corticosteroid treatment can induce skin atrophy, hypopigmentation and transepidermal water loss (TEWL) increase. A new treatment approach was needed to reduce the risk by dermal targeting. For this purpose, Betamethasone valerate (BMV)/Diflucortolone valerate (DFV)-loaded liposomes (220–350 nm) were prepared and incorporated into chitosan gel to obtain adequate viscosity (∼13 000 cps). Drugs were localized in stratum corneum + epidermis of rat skin in ex-vivo permeation studies. The toxicity was assessed on human fibroblast cells. In point of in-vivo studies, pharmacodynamic responses, treatment efficacy and skin irritation were evaluated and compared with previously prepared nanoparticles. Liposome/nanoparticle in gel formulations produced higher paw edema inhibition in rats with respect to the commercial cream. Similar skin blanching effect with commercial creams was obtained via liposome in gels although they contain 10 times less drug. Dermatological scoring results, prognostic histological parameters and suppression of mast cell numbers showed higher treatment efficiency of liposome/nanoparticle in gel formulations in AD-induced rats. TEWL and erythema measurements confirmed these results. Overview of obtained results showed that liposomes might be an effective and safe carrier for corticosteroids in skin disease treatment.
... The formulation's zeta potential can be determined using a zeta metre [15]. The reduction in mean vesicle diameter can vary depending on the ethanol and phospholipid concentrations [16][17][18]. The transition temperature of the vesicular lipid systems can be measured using differential scanning calorimetry, a method that can be used to detect ethanol-skin phospholipid interaction, a property connected to the fluidizing impact of ethanol on the phospholipid bilayers [19]. ...
Ethosomal systems are newer lipid vesicular carriers that have been around for 20 years, but over that period they have grown significantly as a means of transdermal drug delivery. They have a sizable amount of ethanol in them. These nanocarriers carry medicinal substances with various physicochemical qualities throughout the skin and deep skin layers. Since they were created in 1996, ethosomes have undergone substantial investigation; new substances have been added to their original composition, creating new varieties of ethosomal systems. These innovative carriers, which can be added to gels, patches, and lotions, are prepared using several novel methods. In addition to clinical trials, many in vivo models are employed to assess the effectiveness of dermal/transdermal administration. This review focuses on different generation of ethosomes and their comparison with other conventional liposomes.
... The polar head group area of the lipid molecules can interact with ethanol, a known permeation enhancer, to lower the melting point of the SC lipid and increase lipid fluidity and cell membrane permeability (Touitou et al., 2000). The additional ethanol makes the vesicular membranes extremely flexible, which enables the elastic vesicles to force their way through the pores (Liu and Hu, 2007). According to published research, ethosomal systems are more effective than traditional liposomes or hydro-alcoholic solutions at delivering chemicals through the skin in quantity and depth. ...
Topical drug delivery presents a novel substitute to the conventional drug-distribution routes of oral delivery and injection. Apart from the simplicity and non-invasiveness, the skin also serves as a “reservoir” that sustains administration over a period of days. Nanocarriers provide new potential for the treatment of skin disease. The skin’s barrier function offers a considerable obstacle for the potential nanocarriers to infiltrate into the tissue. However, the barrier is partially weakened in case of damage or inflammation, as in the case of skin cancer. Nanoparticles may promote the penetration of the skin. Extensive research has been done into producing nanoparticles for topical distribution; nevertheless, relatively little progress has been achieved in transferring them to the clinic for treating skin malignancies. The prior art features the critical concepts of skin malignancies and techniques in current clinical care. The present review gives a complete viewpoint of the numerous nanoparticle technologies studied for the topical treatment of skin malignancies and outlines the hurdles that hamper its advancement from the bench to the bedside. The review also intends to give knowledge of the routes that control nanoparticle penetration into the skin and their interactions inside the tissue.
... The formulation's zeta potential can be determined using a zeta metre [15]. The reduction in mean vesicle diameter can vary depending on the ethanol and phospholipid concentrations [16][17][18]. The transition temperature of the vesicular lipid systems can be measured using differential scanning calorimetry, a method that can be used to detect ethanol-skin phospholipid interaction, a property connected to the fluidizing impact of ethanol on the phospholipid bilayers [19]. ...
Ethosomal systems are newer lipid vesicular carriers that have been around for 20 years, but over that period they have grown significantly as a means of transdermal drug delivery. They have a sizable amount of ethanol in them. These nanocarriers carry medicinal substances with various physicochemical qualities throughout the skin and deep skin layers. Since they were created in 1996, ethosomes have undergone substantial investigation; new substances have been added to their original composition, creating new varieties of ethosomal systems. These innovative carriers, which can be added to gels, patches, and lotions, are prepared using several novel methods. In addition to clinical trials, many in vivo models are employed to assess the effectiveness of dermal/transdermal administration. This review focuses on different generation of ethosomes and their comparison with other conventional liposomes.
... Various scientific reports revealed that the zeta potential is stable when more positive than of +30 mV or more negative than -30 mV. 24,26,39 Herein, the results revealed that the MF5 transfersomes were more stable than other formulations because their zeta potential was comparatively high. A negative value of zeta potential might be derived from the lipid composition in the formula. ...
Objectives: Nowadays, antioxidants are important for health-related concerns related to acne vulgaris. Acne vulgaris is interrelated with the development of free radicals that interact with cells. Mulberry leaves contain phenolic compounds, including antioxidants such as quercetin. An antioxidant is a scavenger of free radicals. The current study addresses the development of a mulberry leaf extract-based transfersome gel containing quercetin by a thin-layer hydration method for topical antioxidant delivery. The process was optimized by encapsulating the drug in a variety of transfersome formulations.
Materials and Methods: Batch optimization was carried out by particle size and zeta analysis, entrapment efficiency (%), polydispersity index, in vitro drug release, and drug content analysis.
Results: The optimized batch MF5 provided 86.23% entrapment efficiency of quercetin in the vesicles and 95.79% drug release. It furnished a spherical shaped vesicle with an average diameter of 118.7 nm and zeta potential of -45.11 mV. The MG1 formulation provided superior antioxidant activity, drug content, and entrapment efficiency, ex vivo drug release, spreadability, homogeneity, and stability to MG2. The presence of quercetin in the extract and gel formulation was confirmed by using high performance thin layer chromatography.
Conclusion: It is evident from this study that a mulberry leaf extract-based transfersome gel is a promising prolonged delivery system for quercetin and has reasonably good stability characteristics. This research recommends that mulberry leaf extract-based transfersome gel can potentially be used in the treatment of acne vulgaris through a transdermal drug delivery system.
Key words: Transfersomes, mulberry leaves, quercetin, antioxidant activity, transfersome gel
... Topical use of drug through the skin becomes an obstacle because the human skin has an outer layer of stratum corneum that acts as the main barrier of the human body. [1] The formulation of azelaic acid ethosomes by simple method with adding aqueous phase to ethanol solution with concentration between 20% and 45% v/v of phosphatidylcholine (5%, w/w) and azelaic acid (0.2%, w/w), the ratio of drug release was faster than azelaic acid liposome formulation, and the greater concentration of ethanol, the faster release of azelaic acid. [2] Ethosomes as a drug carrier system have both physical (particle or fusion particle) and chemical (chemical interaction of active ingredients during storage) exposed to long-term storage. ...
The ethosomal carrier system can increase the penetration of azelaic acid into the stratum corneum, but ethosomes have both physical (particle aggregation or fusion) and chemical instability (chemical interaction of active ingredients during storage) that are often encountered in long-term storage. The aim of this study is to acquire proethosome formula of azelaic acid with lyoprotectant which has better stability than ethosomes of azelaic acid. Azelaic acid proethosomes were measured its absorbance using an ultraviolet-visible is spectrophotometer at a wavelength of 204 nm to obtain a percentage of entrapment efficiency (EE%). Proethosomes particle size was obtained from the analysis using particle size analyzer. Proethosomes consisting of phosphatidylcholine, ethanol, and propylene glycol were prepared by a thin-layer hydration process. After that, it was added with lyoprotectants such as trehalose, glucose, and mannitol before it was freeze-dried. Physical stability was studied with physical appearance, EE, and particle size. Chemical stability study determined the level of azelaic acid. Both tests were evaluated every 2 weeks for 8-week storage at 4°C and 27°C. Least entrapment efficiency and particle size changes was proethosomes with trehalose addition from 92.06% and 261.0 nm became 68.92% and 957.7 nm at 27°C, meanwhile at 4°C became 77.47% and 439.4 nm. While the highest percentage of azelaic acid content in proethosomes with trehalose was 62.07% (at 27°C) and without lyoprotectant 69.40%. Based on their characteristic, it can be assumed that, azelaic acid proethosomes with trehalose have the best stability than ethosomes and proethosomes with other lyoprotectants.
... 19 Phospholipid-based liposomal formulations have the ability to pass through the lipophilic layers of skin and facilitate drug penetration deep into the stratum corneum. [20][21][22][23] Phospholipids are bilayer membranes that assemble into vesicles and liposomes, based on the lipid composition and concentration. [24][25][26] These carriers can be used to encapsulate both hydrophilic and hydrophobic bioactive molecules into a hydrophobic bilayer vesicle or core of the liposome. ...
Ricinoleic acid (RA) has potential to promote wound healing because of its analgesic and anti‐inflammatory properties. This study investigates the synthesis and characterization of RA liposomes infused in a hydrogel for topical application. Lecithin liposomes containing RA were prepared and incorporated into a chitosan solution and were subsequently cross‐linked with di‐aldehyde β‐cyclodextrin (Di‐β‐CD). Chitosan/Di‐β‐CD concentrations and reaction temperatures were varied to alter gelation time, water content, and mechanical properties of the hydrogel in an effort to obtain a wide range of RA release profiles. Hydrogel cross‐linking was confirmed by spectroscopy, and liposome and carrier hydrogel morphology via microscopy. Chitosan, Di‐β‐CD, and liposome concentrations within the formulation affected the extent of matrix swelling, mechanical strength, and pore and overall morphology. Higher cross‐linking density of the hydrogel led to lower water uptake and slower release rate of RA. Optimized formulations resulted in a burst release of RA followed by a steady release pattern accounting for 80% of the encapsulated RA over a period of 48 hours. However, RA concentrations above 0.1 mg/mL were found to be cytotoxic to fibroblast cultures in vitro because of the oily nature of RA. These formulations promoted wound healing when used to treat full thickness skin wounds (2 cm²) in Wister male rats. The wound contraction rates were significantly higher compared to a commercially available topical cream after a time period of 21 days. Histopathological analysis of the RA‐liposomal chitosan hydrogel group showed that the epidermis, dermis, and subcutaneous skin layers displayed an accelerated yet normal healing compared to control group.
... Liposome is used for transdermal delivery due to its bilayer structure, imparted from phospholipids, which is similar to skin structure [3]. Phospholipids have many advantages as a carrier of active ingredient such as strong tissue affinity, biodegradability and low toxicity [4]. ...
In this study, liposome has been investigated as the potential transdermal carrier for Labisia pumila (Lp) and Ficus deltoidea (Fd). The encapsulation efficiency, zeta potential, particle size and transdermal transport properties of the herbal extracts loaded liposomes were determined to characterize the delivery system. The entrapment efficiency for Lipo-Lp and Lipo-Fd were 35.47 ± 2.71% and 31.23 ± 7.65%, respectively. The average diameter were153.35nm and 131.9nm, respectively and the zeta potential were -47.2 and -46.8, respectively. The permeability and partition coefficient (K) of Lipo-Lp were 1.31cm h-1 and 10.05, respectively and the permeability and partition coefficient (K) of Lipo-Fd were 1.28cm h-1 and 7.62, respectively. Labisia pumila and Ficus deltoidea loaded liposomes showed better transdermal permeation compared to un-encapsulated Labisia pumila and Ficus deltoidea indicative of potential actives herbal cosmetic formulations.
... The zeta potential of PES were almost neutral the values ranging from À1.45 ± 0.84 to À11.8 ± 2.65 mV ( Table 2). Since SPC, a non-ionic surfactant, was used in the preparation of FES, the zeta potential of the formulations remained neutral [26]. Presence of high amounts of ethanol confers the surface a mild negative charge of the vesicles. ...
Androgenetic alopecia, a major cause for baldness, is caused by the deposition of dihydrotestosterone (DHT) at the androgen receptors present in the pilosebaceous unit (PSU). Finasteride (FIN) is a potent 5α-reductase inhibitor capable of preventing the conversion of testosterone to DHT. But, its oral administration in males causes infertility. An attempt was made to prepare ethosomes of FIN with a size range 100–300 nm to enhance its delivery to the PSU. Finasteride loaded ethosomes (FES) were prepared using an ultra-probe sonicator and characterized for its size, morphology, surface charge and entrapment efficiency. The ability of FES to permeate across rat skin and frontal scalp skin of human cadaver was also evaluated. The spherical shaped ethosomes of different batches were in the size range of 107.8 ± 2.50 to 220.4 ± 6.92 nm and showed good permeation across rat skin and frontal scalp skin of human cadaver when compared to the unencapsulated FIN. The results portrayed the ability of FES to permeate across the stratum corneum to reach the PSU of the hair follicle. Although additional use of permeation enhancer increases the permeation of FIN across the skin, its addition may not be a favourable option for the deposition of ethosomes in the PSU.
... The nature of the liposome macrostructure would allow it to pass through lipophilic layers of skin and facilitate the drug penetration to the top layer of the stratum corneum cells [21]. However, conventional liposomes are inherently unstable and inclined to fuse into larger aggregates hard to transport through the skin layers https://doi.org/10.1016/j.ijbiomac.2017.09.031 0141-8130/© 2017 Elsevier B.V. All rights reserved. ...
The chemistry of pyrazoles has gained increasing attention due to its diverse pharmacological properties such as antiviral, antagonist, antimicrobial, anticancer, anti-inflammatory, analgesic, anti-prostate cancer, herbicidal, acaricidal and insecticidal activities. 1-phenyl pyrazole-3, 5-diamine, 4-[2-(4-methylphenyl) diazenyl] and 1H- pyrazole-3 (1), 5-diamine, 4-[2-(4-methylphenyl) diazenyl] (2) were synthesized, characterized and encapsulated into liposomal chitosan emulsions for textile finishing. The chemical modifications of cotton fabrics were demonstrated by infrared analysis. Retention of the fabric mechanical properties was investigated by reporting the tensile strength values. Synthesized pyrazol-based compounds were screened for cytotoxicity against skin fibroblast cell line and showed very limited toxicity for both compounds. Antimicrobial potentials of the treated cotton fabrics were tested against bacterial strains E. coli ATCC 8379 and Staphylococcus aureus ATCC.
... Precipitation occurred soon after preparation for formulations containing 10 and 60% ethanol and after 1 week in the case of formulations prepared using 50% v/v ethanol. Higher zeta potentials of −33.1 to −35.6 mV were measured for ethosome formulations containing 20-40% v/v ethanol and 3% SPC, indicating higher stability [21,22]. The higher stability of these formulations is attributed to modification of the net negative surface charge in the presence of ethanol thereby enhancing charge stabilization of the vesicles due to electrostatic repulsion and delaying the formation of aggregates [17]. ...
Ethosome formulations containing phenylethyl resorcinol (PR) were developed. The formulation was produced from 0.5% w/v PR, 0.5% w/v cholesterol from lanolin, 3% w/v L-α-phosphatidylcholine from soybean, 30% v/v absolute ethanol, and water up to 100% v/v. It was characterized by a vesicular size of 389 nm, low polydispersity index of 0.266, zeta potential of − mV, high PR entrapment efficiency of 71%, and good stability on storage at 4 and 30°C at 75% RH for 4 months. In vitro studies using pig skin revealed that permeation coefficient of PR from ethosomes was significantly higher than that from liposomes. In vitro retention profiles showed that PR accumulation in pig skin following application of ethosome formulations was 7.4-, 3.3-, and 1.8-fold higher than that achieved using liposomes, 20% propylene glycol solution, and 30% hydroethanolic solution, respectively. An inhibition value of around 80% was measured for antityrosinase activity of PR in pig skin. Consistently, ethosomes exhibited higher tyrosinase inhibition activity and melanin content reduction when compared to other formulations in B16 melanoma cells. Ethosomes did not cause acute dermal irritation in albino rabbits. These findings demonstrate that ethosomes are capable of delivering PR into the skin efficiently and hold promise for topical application of skin lightening products.
... Such accumulation of the extract/ phytoconstituent in the skin acting as depot for a longer time is good because it helps sustain release of actives in the epidermis over a period of time and makes it suitable for cosmetic products that are meant to act upon the skin. This property of the extract-phospholipid cream can be attributed to the fact that since phospholipids are main components of stratum corneum, they can transport drugs to target skin cells [19] . ...
Photoprotectives in skin-care is essential to prevent oxidative stress induced by long term exposure to UV. Phyllanthus emblica fruit extract contains polyphenols that are potent antioxidants. But polyphenols have limited penetration into skin therefore its topical use, as a photoprotectant, is ineffective. This study aims to develop a phospholipid complex of amla extract that enhances the delivery of polyphenols into the skin. The amla extract phospholipid developed, had an entrapment efficiency of 94.03±0.10 %. The characterization studies showed that constituents of amla extract successfully formed a complex with phospholipids. The complex was incorporated into a cream formulation, which was found to be stable. The ex-vivo diffusion studies of cream showed that administration of the amla extract via phospholipid complexes gave better skin retention compared to the conventional cream. Thus, phospholipid complex of amla extract gave a prolonged antioxidant effect compared to the conventional cream.
... Among the formulations, liposomal batch L4 exhibited highest ζ value of -37±0.4 mV due to surface charge imparting nature of stearic acid [34,35]. This indicated moderate stability of the prepared liposomes. ...
Background:
The goal of effective treatment for dermal fungal infections could be highly beneficial by the delivery of antifungal drugs on skin from liposomal application. Topical delivery involves minimizing the flux of the drug through the skin while maximizing its retention on the skin. The aim of the present work was the investigation of the effects of lipids and cholesterol for the development of liposomal formulations as potential carriers for antifungal agent terbinafine HCl. Phospholipon 90H (hydrogenated phosphatidylcholine) and dimyristoylglycero-3-phosphocholine (DMPC) along with cholesterol were used for preparation of liposomes by ethanol injection method and characterized for drug content, entrapment efficiency, size, zetapotential, vesicle morphology, stability, FTIR, in vitro and ex vivo drug retention studies.
Results:
Drug entrapment ranged between 39.46±0.91% to 70.39±0.71%. Vesicles showed good morphological characters with a narrow size distribution, in the size range of 206.9 to 344.8 nm. Gum karaya gel loaded with liposomal dispersion showed prolonged drug retention on the rat skin during ex vivo studies compared to liposomal dispersion and gum karaya plain gel loaded with drug.
Conclusion:
The prolonged retention of drug by the gum karaya gel loaded with liposomal dispersion could effectively exhibit the antifungal activity for prolonged periods for cutaneous delivery.
... [22,23] The transition temperature of the vesicular lipid systems can be determined by using differential scanning calorimetry, which also detects ethanol-skin phospholipid interaction, a characteristic attributed to the fluidizing effect of ethanol on the phospholipid bilayers. [24] The entrapment efficiency of ethosomes can be measured by the ultracentrifugation technique. The ability of ethosomes to efficiently entrap lipophilic and hydrophilic drugs can be explained by the high degree of lamellarity and the presence of ethanol in the vesicles. ...
The main disadvantage of transdermal drug delivery is the poor penetration of most compounds into the human skin. The main barrier of the skin is located within its uppermost layer, the stratum corneum (SC). Several approaches have been developed to weaken this skin barrier. One of the approaches for increasing the skin penetration of drugs and many cosmetic chemicals is the use of vesicular systems, such as, liposomes and ethosomes. Ethosomes are phospholipid-based elastic nanovesicles containing a high content of ethanol (20-45%). Ethanol is known as an efficient permeation enhancer and has been added in the vesicular systems to prepare elastic nanovesicles. It can interact with the polar head group region of the lipid molecules, resulting in the reduction of the melting point of the stratum corneum lipid, thereby increasing lipid fluidity and cell membrane permeability. The high flexibility of vesicular membranes from the added ethanol permits the elastic vesicles to squeeze themselves through the pores, which are much smaller than their diameters. Ethosomal systems are much more efficient in delivering substances to the skin in the terms of quantity and depth, than either conventional liposomes or hydroalcoholic solutions. The scope of this small review is to introduce the novel concept of ethosomes and to describe some approaches and mechanisms of stimulating topical and transdermal products with ethosomes.
... As expected, the skin permeability of Lipo-AdCbl-gel was higher than that of AdCbl-gel in a permeability study using excised mouse skin. Since keratinocytes of the stratum corneum are composed of phosphatidylcholine and sphingomyelin (Cevc et al. 1996;Liu and Hu 2007), and liposome has strong tissue affinity for the stratum corneum due to the phospholipid in the liposome (Benson 2005;Barichello et al. 2006), Lipo-AdCbl appears to induce greater skin permeability of the stratum corneum. The hydrogel of the Lipo-AdCbl-gel contains various chemical enhancers such as propylene glycol, ethanol and glycerin (Spernath et al. 2008), which increases permeability across the stratum corneum (Valenta and Auner 2004). ...
Topical vitamin B12 was shown to be effective for atopic dermatitis. However, vitamin B12 itself is light sensitive and has low skin permeability, thus reducing its therapeutic effectiveness. In the present study, we prepared a liposomal hydrogel of adenosylcobalamin (AdCbl), a vitamin B12 derivative, and investigated possible beneficial effects of AdCbl on atopic dermatitis using an NC/Nga murine atopic dermatitis model. AdCbl was loaded into liposomes prepared by a thin film hydration method using a pH gradient method that employed citric acid buffer solution. This resulted in AdCbl-loaded liposomes that were 106.4 +/- 2.2 nm in size. The loading efficiency was 40% (of the initial AdCbl amount). Lipo-AdCbl had enhanced skin permeability, being about 17-fold compared with AdCbl-gel. Topical administration of Lipo-AdCbl-gel to 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis-like skin lesions in NC/Nga mice ameliorated lesion intensity scores, dorsal skin thickness, and total serum IgE in a concentration-dependent manner. Other preparations, including AdCbl solution, AdCbl cream, liposomes alone, and a mixture of AdCbl solution and liposomes had little effect. Taken together, our findings indicate that Lipo-AdCbl-gel has protective effects against atopic dermatitis symptoms, and suggest that it may be of benefit in the treatment of human inflammatory skin diseases.
The emergence of lipid nanovesicles (LNVs), like liposomes, transferosomes, and ethosomes, strengthens transdermal drug delivery. The composition of lipid vesicles is similar to that of skin, so these can easily penetrate through the skin. Modifications in the design of lipid vesicles help enhance skin permeation; therefore, dose reduction is possible. Ultradeformable vesicles are superior to conventional lipid vesicles because of their better stability. Various methods used to prepare LNVs are the classical cold method, ethanol injection method, ether injection method, and film hydration method. The method of preparation is crucial because it drastically affects the characteristics of vesicles. The vesicles are evaluated for their physicochemical and biological properties. Since vesicular systems are more susceptible to physical, chemical, and biological degradation, their stability is critical and challenging. The transdermal applications of LNVs spread across all areas like antifungal, anti-inflammatory, and anticancer drugs and the delivery of proteins and peptides.
In recent years, more and more information has appeared with the development of network technology. To manage the information effectively has become an important research direction. Under this background, the information management application system has developed rapidly. The sports information management application includes information collection, processing and collation. Using information management application system to manage all work in the field of sports is an important way to realize the sports informatization. At first, this article introduces the sports information management application system development principles which include systemic principle, standardized principle and cooperative principle. Then under the guidance of these principles, a set of school sports information management application system which is developed by the authors is introduced. This system uses the combination of Client/Server mode and Browser/Server mode. It contains fours subsystems: the sports teaching management subsystem, the physical test management subsystem, the sports competition subsystem and the system management subsystem.
We propose a numerical method for solving the problem of taking a nonlinear system to the zero state while minimizing a nonnegative convex functional. The particular cases include the problem of minimizing the consumption of resources or energy. The method is based on the maximum principle and approximations of bodies with some families of simplices. The properties of coverings of bodies with simplices enable us to justify the convergence of the method.
Five different methods were tested and compared to prepare danofloxacin mesylate liposomes, the ammonium sulfate gradient method with freeze-thawing steps was validated as the best one; the optimal preparation condition confirmed by orthogonal experiment was as follows: EPC-CH ratio was 3 : 2 and 2.6% SA was added to gain the positive electricity; drug-lipoid was 2 : 5, the concentration of ammonium sulfate was 250 mmol · L−1, water-oil ratio was 1 : 5, and they were incubated at 35°C for 15 min. The prepared liposome products were ivory white semitransparent suspension, the electron microscope appearance was intact and globular or globular-like vesicles with uniformed distribution; the particle size was centralized from 3 to 7 μm, zeta-electric potential valued+ (15.92±1.49) mV, pH valued 6.02±0.09; HPLC method was established in quantitative analyses of danofloxacin and reverse dialysis with RP-HPLC method was validated for determination of entrapment efficiency. The entrapment efficiency results were all above 90%. They were stored at 4°C with satisfied stability. Six months later, the appearance, characters and entrapment efficiency were almost with no change.
Introduction:
Skin disorders will continue to cause complications in patients. At present, there is an expansion of research into dermatologic treatment due to a critical need for new treatment options to treat skin diseases.
Areas covered:
The skin itself provides a natural barrier against particle penetration for topical delivery. However, it also offers a potential approach for the delivery of therapeutics, especially in diseased skin and via the openings of hair follicles. Recent innovation might be achieved in the field of dermatological treatment with improvement in the dermal localization of bioactives into the affected skin region, via novel nanocarriers that deliver the drugs directly to the target cells. After application, these nanocarriers can penetrate through the stratum corneum into viable skin and accumulate at the target site. However, noteworthy uptake does occur after damage and in certain diseased skin.
Expert opinion:
Skin-targeted topical delivery by means of nanosystems, in order to produce sustained release and maintain a localized effect, will result in an effective treatment of various life-threatening dermatological conditions. In addition, research continues into the interactions between novel particles, skin and skin lipid, and the influence of particle composition on drug distribution within the skin strata.
The topical application of all-trans retinoic acid (ATRA) is an effective treatment for several skin disorders, including photo-aging. Unfortunately, ATRA is susceptible to light, heat, and oxidizing agents. Thus, this study aimed to investigate the ability of polymeric micelles prepared from polyethylene glycol conjugated phosphatidylethanolamine (PEG-PE) to stabilize ATRA under various storage conditions. ATRA entrapped in polymeric micelles with various PEG and PE structures was prepared. The critical micelle concentrations were 97-243 μM, depending on the structures of the PEG and PE molecules. All of the micelles had particle diameters of 6-20 nm and neutral charges. The highest entrapment efficiency (82.7%) of the tested micelles was exhibited by ATRA in PEG with a molecular weight of 750 Da conjugated to dipalmitoyl phosphatidylethanolamine (PEG(750)-DPPE) micelles. The PEG(750)-DPPE micelle could significantly retard ATRA oxidation compared to ATRA in 75% methanol/HBS solution. Up to 87% of ATRA remained in the PEG(750)-DPPE micelle solution after storage in ambient air for 28 days. This result suggests that PEG(750)-DPPE micelle can improve ATRA stability. Therefore, ATRA in PEG(750)-DPPE micelle is an interesting alternative structure for the development of cosmeceutical formulations.
Transdermal drug delivery system has been accepted as potential non-invasive route of drug administration, with advantages of avoidance of the first-pass metabolism, sustained therapeutic action and better patient compliance, though, its prevalent use is restricted due to excellent impervious nature of skin. It is the greatest challenge for researchers to surmount the inherent limitations imposed by stratum corneum of skin, for enhanced transdermal drug delivery to achieve systemic therapeutic concentration. Thus, many approaches have been attempted to perturb skin barrier and enhance the transdermal delivery of drug. The major approaches for enhancing transdermal delivery are physical enhancers (ultrasound, iontophoresis, electroporation, magnetophoresis, microneedle), vesicles, particulate systems (liposome, niosome, transfersome, microemulsion, solid lipid nanoparticle) and chemical enhancers (sulphoxides, azones, glycols, alkanols, terpenes etc.). The present review explores recent patents on techniques employed to breach the skin barrier for drug permeation along with their penetration enhancement mechanisms.
The use of phospholipids (PL) as surfactants in micellar systems and microemulsions offers many advantages as drug delivery vehicles. PL are commonly used in combination with other non-food surfactants with cosolvents and cosurfactants to form a cascade of delivery structures. In this work, we incorporated phosphatidylcholine (PC) in our unique U-type water-dilutable phase diagrams exhibiting large isotropic regions of nanostructures. The nanometric liquid structures were prepared from food-grade emulsifiers. We formed water-free concentrates with PC that are fully diluted with water to form a variety of unusually structured nanodroplets. Due to the uniqueness of their composition, the designed concentrates derived from the nature of the oil phase, type of surfactants, and cosurfactants were characterized and found to be direct micelles (rather than inverse micelles), with the surfactant headgroups convexed toward the hydrophilic phase away from the micelle's core, even in the absence of water. The concentrates tend to self-assemble upon adding water to form O/W microemulsions even with small amounts of water (water-poor compositions of 0-20 wt% water). Upon further dilution with water the swollen micelles retain the oil as the inner phase. Multi-component compositions with two types of hydrophilic surfactants were investigated. The most significant enhancement in the total isotropic region was obtained by decreasing the triacetin and PC content in the system. We explored, by varying the nature of the headgroups and the nature and length of the lipidic (lipophilic) tails of the PL, the dilution capabilities of each of the systems.
In recent years, transparent dispersions or diluted milks have been used as sunscreens. These products contain water-soluble sunscreen agents, and quite frequently are washed away from the skin. However, O/W microemulsions are now being prepared as transparent vehicles for sunscreens. They are waterproof, nonsticky, and easily spreadable. The microemulsions are prepared by using pseudoternary diagrams, by combining lipids with surfactant blends and a polar phase. Soya lecithin and decylpolyglucose produce transparent systems with the lowest percentage of surfactants. These microemulsions contain 4-methylbenzilidene camphor or octylmethoxycinnamate as sunscreen agents. Cyclomethicone, menthol, and allantoin give products a good skin feel, and stearyl methicone gives the waterproof effect. These systems show a Newtonian flux. Little permeation of the sunscreens' trough lipophilic and hydrophilic membrane is evidenced.
An o/w microemulsion formulated using lecithin and an alkyl glucoside as mild, non-irritant surfactants was proposed as a cosmetic vehicle for arbutin and kojic acid, naturally occurring whitening agents. After assessing the physicochemical stability of the microemulsion in the presence and absence of whitening agents, several perfumed compositions, developed using fragrant molecules of natural or synthetic origin, were introduced, and the olfactory impact of the perfumed microemulsion was evaluated. The photostability to UVB irradiation of both whitening agents was determined in aqueous solutions and in microemulsions, and also in the presence of the perfumed compositions. The stability of arbutin and kojic acid was higher in microemulsions than in aqueous solutions, and only in some cases did the presence of odorous molecules appear to influence it: linalool exerted some protective effect towards kojic acid photodegradation.
Cetirizine, an effective, minimally sedating, second-generation H1-antihistamine is widely used orally to treat allergic skin disorders. This study was performed to assess the peripheral H1-antihistaminic activity and extent of systemic absorption of cetirizine from liposomes applied to the skin. Cetirizine was incorporated into small unilamellar vesicles (SUV) and multilamellar vesicles (MLV) prepared using L-alpha-phosphatidylcholine hydrogenated (HPC), and into Glaxal Base (GB) as the control. In a randomized, crossover study, each formulation, containing 10 mg of cetirizine, was applied to the depilated backs of 6 rabbits (3.08 +/- 0.05 kg). Histamine-induced wheal tests and blood sampling were performed before cetirizine application and at designated times for up to 24 hours afterwards. Compared with baseline, histamine-induced wheal formation was suppressed by cetirizine in SUV only at 24 hours, in MLV from 0.5 to 24 hours, and in GB from 0.5 to 8 hours (P < or = .05). Wheal suppression by cetirizine in SUV at 24 hours (91.7% +/- 5.2%) and in MLV from 1 to 24 hours (93.8% +/- 2.2% to 76.2% +/- 6.5%) was greater than in GB (36.5% +/- 7.4% to 60.6% +/- 14.2%) from 1 to 24 hours (P < or = .05). Faster onset, as well as greater and more persistent suppression was obtained from cetirizine in MLV. Plasma cetirizine concentrations from MLV (area under the curve [AUC] of 221.2 +/- 42.3 ng x hr/mL) were lower than from GB (AUC of 248.3 +/- 34.6 ng.hr/mL). In this model, cetirizine from MLV had excellent topical H(1)-antihistamine activity, while systemic exposure was reduced, compared with cetirizine from GB.
The aim of this work was the evaluation of various ethosomal suspensions made up of water, phospholipids and ethanol at various concentrations for their potential application in dermal administration of ammonium glycyrrhizinate, a useful drug for the treatment of various inflammatory-based skin diseases. Physicochemical characterization of ethosomes was carried out by photon correlation spectroscopy and freeze fracture electron microscopy. The percutaneous permeation of ammonium glycyrrhizinate/ethosomes was evaluated in vitro through human stratum corneum and epidermis membranes by using Franz's cells and compared with the permeation profiles of drug solutions either in water or in a water-ethanol mixture. Reflectance spectrophotometry was used as a non-invasive technique to evaluate the carrier toxicity, the drug permeation and the anti-inflammatory activity of ammonium glycyrrhizinate in a model of skin erythema in vivo on human volunteers. Ethosomal suspensions had mean sizes ranging from 350 nm to 100 nm as a function of ethanol and lecithin quantities, i.e., high amounts of ethanol and a low lecithin concentration provided ethosome suspensions with a mean size of approximately 100 nm and a narrow size distribution. In vitro and in vivo experiments were carried out by using an ethosome formulation made up of ethanol 45% (v/v) and lecithin 2% (w/v). The ethosome suspension showed a very good skin tolerability in human volunteers, also when applied for a long period (48 h). Ethosomes elicited an increase of the in vitro percutaneous permeation of both methylnicotinate and ammonium glycyrrhizinate. Ethosomes were able to significantly enhance the anti-inflammatory activity of ammonium glycyrrhizinate compared to the ethanolic or aqueous solutions of this drug. Some in vivo experiments also showed the ability of ethosome to ensure a skin accumulation and a sustained release of the ammonium glycyrrhizinate.
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 °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.
We characterised biological properties of novel formulations of two low-potency glucocorticosteroids, dexamethasone and hydrocortisone, which have an equivalent dose ratio of 1:50 in vasoconstriction tests. The rate of such carrier-mediated, mainly non-diffusive glucocorticosteroids transport with very deformable lipid vesicles (Transfersomes®) through the skin, and the corresponding cutaneous drug biodistribution data, were complemented with the drug bio-efficacy studies. The minimum effective drug dose that reduces arachidonic acid-induced murine ear oedema by 50% was used as one bioactivity indicator. The minimum drug amount ensuring such an effect in mouse skin decreases appreciably when a corticosteroid is applied epicutaneously with very deformable vesicles rather than a lotion or a crème. Specifically, the minimum effective dose for hydrocortisone in very deformable carriers is 2–3 μg cm−2 whereas for the crème- or lotion-like preparations at least 10 μg cm−2 is required. Such three- to fivefold relative increase of hydrocortisone potency is accompanied by at least 13%, and more often >20%, absolute drug potency enhancement. The delivery of hydrocortisone with very deformable carriers moreover prolongs the suppression of the drug-induced oedema nearly 2-fold (to ∼24 h per application). The effective dose of dexamethasone delivered with very deformable vesicles into murine skin is reduced >10 times compared with the crème- or lotion-based products. Specifically, less than 0.1 μg cm−2 dexamethasone in very deformable vesicles suppresses the arachidonic acid-induced murine ear oedema >50%, on the average. Dexamethasone use on the skin in such vesicles extends the duration of drug action fourfold, compared with a commercial crème, i.e. to >48 h per application. Epicutaneous use of glucocorticosteroids in very deformable vesicles also diminishes such drug's abrasion sensitivity and may increase the general robustness of drug effect. Lower frequency of skin treatment, which ensures adequate biological response, is a result of this. Topical corticosteroid delivery with very deformable vesicles, Transfersomes®, thus improves the therapeutic risk–benefit ratio, arguably due to better targeting into and longer drug presence in the skin.
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.
The influence of liposome composition on bilayer fluidity and its effect on the percutaneous absorption into the skin were investigated. Liposomes formed with saturated or unsaturated phospholipids (H-PC or PC) with varying amounts of cholesterol were prepared and their penetration behaviour into the stratum corneum was followed up by means of the stripping method. The order and dynamics of the hydrophobic domain of the vesicles were studied using electron paramagnetic resonance (EPR) methodology. Phospholipid composition and the amount of cholesterol exert a considerable influence on the penetration behaviour of the probe encapsulated in the liposomes. This behaviour is closely related to the fluidity characteristics of these liposomes studied by EPR. Therefore, a penetration mechanism of the vesicles into the skin, based on the incorporation of lipids into the skin lipids and on fluidity behaviour, is suggested.
To clarify the effect of the surface charge of liposomes on percutaneous absorption, the permeation of liposomal drugs through rat skin was investigated in vitro and in vivo. Liposomes were prepared using egg yolk lecithin (EPC, phase transition temperature, -15 to -17 degrees C), cholesterol and dicetylphosphate (DP) or stearylamine (SA) (10:1:1, mol/mol). Also examined was the penetration behavior of positively and negatively charged liposomes, using a fluorescent probe (Nile Red). The in vitro penetration rate of melatonin (MT) entrapped in negatively charged liposomes was higher than that of positively charged ones (p<0.05). When the percutaneous absorption of ethosuximide (ES) encapsulated was estimated in vivo, the absorption of ES from negatively charged liposomes was slightly higher than that from positively charged liposomes. Additionally, the absorption of ES from both types of liposomes was superior to that from the lipid mixtures consisting of the same composition as the vesicles. The percutaneous absorption of betahistine (BH) from a gel formulation containing negatively charged liposomes of BH was much more than that from the formulation with positively charged ones, with 2-fold higher AUC (p<0.05). Histological studies revealed that the negatively charged liposomes diffused to the dermis and the lower portion of hair follicles through the stratum corneum and the follicles much faster than the positive vesicles at the initial time stage after application. Thus, the rapid penetration of negatively charged liposomes would contribute to the increased permeation of drugs through the skin.
The potential use of ultradeformable and standard liposomes as skin drug delivery systems was investigated in-vitro. An improved experimental design gave a good measure for skin deposition of drug. This avoided the contamination that can occur due to incomplete washing of the donor before direct determination of the amount of drug in the skin. The design used aqueous ethanolic receptor which is believed to diffuse into skin, disrupting deposited liposomes (if any) and thus releasing both bound and free drug. The receptor fluid was refined by testing different concentrations of ethanol. The applied dose was also optimized. Using the improved design and the optimum dose, an ultradeformable formulation was compared with four traditional liposomes for skin delivery of 5-fluorouracil (5-FU). The best receptor was 50% aqueous ethanol and the optimum dose was 20 microL. The ultradeformable formulation was superior to standard liposomes in the skin delivery of 5-FU. Of the traditional liposomes, the non-rigid preparation was the best. However, stabilization of the liposome membrane with cholesterol abolished the benefit of this non-rigid preparation. It was concluded that ultradeformable vesicles are promising agents for skin delivery of drugs.
The in vitro transdermal absorption of apomorphine from microemulsions was studied using the skin of the hairless mouse as a membrane. Two microemulsions (no. 1 and 2) were prepared and thickened both containing 3.9% of apomorphine hydrochloride. The lipophilicity of the drug was increased by forming apomorphine-octanoic acid ion-pairs. The fluxes of the drug from the microemulsions through hairless mouse skin were 100 microg h(-1) cm(-2) from no. 1 and 88 microg h(-1) cm(-2) from no. 2. Apomorphine in microemulsions, protected from light with antioxidants, showed no degradation for up to 6 months.
DNA vaccines have been shown to elicit both broad humoral and cellular immune responses. Needle-free injection devices and the gene gun have been used to deliver these DNA vaccines to dendritic cells in the viable skin epidermis with some success. However, more cost-effective and dendritic cell (DC)-targeted immunization strategies are sought. To this end, a nanoengineered genetic vaccine for simple topical application was developed. Expressed beta-galactosidase was used as a model antigen. Plasmid DNA was coated on the surface of preformed cationic nanoparticles engineered directly from warm oil-in-water (O/W) microemulsion precursors comprised of emulsifying wax as the oil phase and CTAB as a cationic surfactant. Mannan, a DC ligand, was coated on the nanoparticles with and without entrapped endosomolytic agents, dioleoyl phosphatidylethanolamine (DOPE) and cholesterol. In-vitro cell transfection studies were performed to confirm transgene expression with these pDNA-coated nanoparticles. An in-vitro Concanavalin A (ConA) agglutination assay confirmed the presence of mannan on the surface of nanoparticles. The humoral and proliferative immune responses were assessed after topical application of these nanoengineered systems to the skin of shaved Balb/C mice. All pDNA-coated nanoparticles, especially the mannan-coated pDNA-nanoparticles with DOPE, resulted in significant enhancement in both antigen-specific IgG titers (16-fold) and splenocyte proliferation over 'naked' pDNA alone.
The potential application of highly biocompatible o/w microemulsions as topical drug carrier systems for the percutaneous delivery of anti-inflammatory drugs, i.e. ketoprofen, was investigated. Microemulsions were made up of triglycerides as oil phase, a mixture of lecithin and n-butanol as a surfactant/co-surfactant system and an aqueous solution as the external phase. To evaluate the percutaneous enhancing effect of oleic acid, this compound was used as a component of some o/w microemulsions. The topical carrier potentialities of lecithin-based o/w microemulsions were compared with respect to conventional formulations, i.e. a w/o emulsion, a o/w emulsion and a gel. Physicochemical characterisation of microemulsions was carried out by light scattering and zeta potential analyses. Microemulsions showed mean droplet size < 35 nm and a negative zeta potential, that is -39.5 mV for the oleic acid-lecithin microemulsion and -19.7 mV for the lecithin-based microemulsion. The percutaneous adsorption of the various topical formulations was evaluated through healthy adult human skin, which was obtained from abdominal reduction surgery. Ketoprofen-loaded microemulsions showed an enhanced permeation through human skin with respect to conventional formulations. No significant percutaneous enhancer effect was observed for ketoprofen-loaded oleic acid-lecithin microemulsions. The human skin tolerability of various microemulsion formulations was evaluated on human volunteers. Microemulsions showed a good human skin tolerability.
The purpose of the present study was to determinate the significance of ion pairing on the topical permeation of retinoic acid (R.A) using microemulsions as delivery vehicles. Phenylalanine methyl ester, phenylalanine ethylester, histidine methyl ester, tryptophan methyl ester and valine methyl ester were used as counter ions. Results of diffusion studies through polydimethylsiloxane membrane (PDMS) indicate that retinoic acid permeation from ethanol-pH 6.4 buffer mixture significantly increased in the presence of counter ions. A linear relationship was found between apparent partition coefficients and permeation coefficients. The highest values were with valine methyl ester and phenylalanine ethyl ester. In order to develop alternative formulations for topical administration of R.A, microemulsions were evaluated as delivery vehicles. Oil-in-water (O/W) and water-in-oil (W/O) microemulsion formulations were prepared using water, isopropyl myristate, lecithin, caprylyl-capryl glucoside and ethanol or 1,2 hexanediol. Experiments with PDMS membranes showed decreasing permeabilities of R.A from microemulsions in the presence of counter ions. This was related to the increased lipophilicity and different vehicle membrane affinity of the ion pairs The ability of the systems to deliver R.A through the skin was evaluated in vitro using pig-skin. R.A permeabilities were much lower with microemulsions than with solution, while a large increase in R.A skin deposition was observed only from O/W microemulsions in the presence of counter ions. The depth of skin accumulation was below 100 microm after 24 h application. The results suggest that O/W microemulsions containing a counter ion can be used to optimise drug targeting without a concomitant increase in systemic absorption.
In the present study, the influence of vesicle size on the penetration of two fluorescently labeled substances into the human skin was investigated. For the measurements either a hydrophilic fluorescent compound [carboxyfluorescein (CF)] or a lipophilic one [1,1'-dioctadecyl-3,3,3',3'-tertramethylindocarbo-cyanine perchlorate (DiI)] were encapsulated into vesicles. Liposomal formulations were prepared by extruding the vesicles through polycarbonate membrane filters with pores of different sizes. In vitro penetration studies into human abdominal skin were performed by using the Franz diffusion cell and a standardized skin stripping technique in attempt to find an optimum size for topical drug delivery by liposomes. Confocal laser scanning microscopy (CLSM) was used to visualize the effect of penetration ability of liposomal DiI. The maximum DiI fluorescence in the skin was observed with smaller liposomes of 71 nm diameter. The liposomes with a size of 120 nm diameter showed statistically enhanced penetration of CF into the skin as compared to larger ones. The results indicated that the CF penetration was inversely related to the size of the liposomes, which was confirmed by the data of the confocal laser scanning microscopy studies.
Deformable liposomes were prepared to investigate the effectiveness of dermal administration of methotrexate (MTX). The phospholipids used to prepare the liposomes were soybean lecithin (PC) or hydrogenated lecithin (HPC) and dipotassium glycyrrhizinate (KG) as surfactant. The lipid/KG ratio (w/w) was 2:1 and 4:1. Liposomes size, entrapment efficiency and MTX release through dialysis membrane were determined and the interaction between MTX and liposomes was investigated using differential scanning calorimetry. The MTX amount permeated through pig skin were three- to four-fold higher using liposomes containing KG compared to those from water solution or normal liposomes. No significant differences were observed between PC-KG liposomes and HPC-KG liposomes. At the end of the skin permeation assay using deformable liposomes, up to 50% of the administered dose was found in the skin. This capability depends on the self-regulating carrier deformability. These results suggest that liposomes containing KG may be of value for the topical administration of MTX in the treatment of psoriasis.
The main objective of the present work was to investigate the dermal and intracellular delivery of bacitracin, a model polypeptide antibiotic, from ethosomes. Bacitracin and fluorescently labeled bacitracin (FITC-Bac) ethosomes were characterized for shape, lamellarity, fluidity, size distribution and entrapment capacity by scanning electron microscopy (SEM), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), dynamic light scattering (DLS) and ultracentrifugation, respectively. Confocal laser scanning microscopy (CLSM) experiments revealed that ethosomes facilitated the copenetration of antibiotic and phospholipid into cultured 3T3 Swiss albino mice fibroblasts. These results, confirmed by data obtained in fluorescent-activated cell sorting (FACS) experiments, suggest that ethosomes penetrate cellular membrane releasing the entrapped molecule within cells. Additional work was focused on skin permeation behavior of FITC-Bac from ethosomal systems in in vitro and in vivo experiments through human cadaver and rat skin, respectively. These studies demonstrated that the antibiotic peptide was delivered into deep skin layers through intercorneocyte lipid domain of stratum corneum (SC). Occlusion had no effect on the permeation profile of the drug from ethosomes in in vitro experiments. Efficient delivery of antibiotics to deep skin strata from ethosomal applications could be highly beneficial, reducing possible side effects and other drawbacks associated with systemic treatment. Furthermore, ethosomal delivery systems could be considered for the treatment of a number of dermal infections, requiring intracellular delivery of antibiotics, whereby the drug must bypass two barriers: the SC and the cell membrane.
Linoleic acid (LA) is known to have a whitening effect on hyperpigmented skin, and is encapsulated in liposomes for topical application because of its low solubility in aqueous solution, although the effect of liposomalization of LA on the whitening activity has not been evaluated. In the present study, we evaluated the effect of liposomalization on the whitening activity of LA by using LA in ethanol, hydrogel containing LA, and hydrogel containing liposomal LA towards the UV-stimulated hyperpigmented dorsal skin of brownish guinea pigs. The whitening effect was far greater for hydrogel containing liposomal LA (0.1% w/w as a final concentration of LA) than for free LA in ethanol or hydrogel containing LA. Next, the whitening effect of LA was examined with UV-stimulated hyperpigmented human upper arm skin by using a hydrogel containing liposomal LA (0.1% LA) and non-liposomal LA (3.0, 10.0% LA). Liposomal LA (0.1%) showed a whitening effect comparable to 10.0% non-liposomal LA and was far more effective than 3.0% non-liposomal LA. These results indicate that liposomal formulations are favorable for the transdermal application of LA.
We characterised biological properties of novel formulations of two low-potency glucocorticosteroids, dexamethasone and hydrocortisone, which have an equivalent dose ratio of 1:50 in vasoconstriction tests. The rate of such carrier-mediated, mainly non-diffusive glucocorticosteroids transport with very deformable lipid vesicles (Transfersomes) through the skin, and the corresponding cutaneous drug biodistribution data, were complemented with the drug bio-efficacy studies. The minimum effective drug dose that reduces arachidonic acid-induced murine ear oedema by 50% was used as one bioactivity indicator. The minimum drug amount ensuring such an effect in mouse skin decreases appreciably when a corticosteroid is applied epicutaneously with very deformable vesicles rather than a lotion or a crème. Specifically, the minimum effective dose for hydrocortisone in very deformable carriers is 2-3 microg cm(-2) whereas for the crème- or lotion-like preparations at least 10 microg cm(-2) is required. Such three- to fivefold relative increase of hydrocortisone potency is accompanied by at least 13%, and more often >20%, absolute drug potency enhancement. The delivery of hydrocortisone with very deformable carriers moreover prolongs the suppression of the drug-induced oedema nearly 2-fold (to approximately 24 h per application). The effective dose of dexamethasone delivered with very deformable vesicles into murine skin is reduced >10 times compared with the crème- or lotion-based products. Specifically, less than 0.1 microg cm(-2) dexamethasone in very deformable vesicles suppresses the arachidonic acid-induced murine ear oedema >50%, on the average. Dexamethasone use on the skin in such vesicles extends the duration of drug action fourfold, compared with a commercial crème, i.e. to >48 h per application. Epicutaneous use of glucocorticosteroids in very deformable vesicles also diminishes such drug's abrasion sensitivity and may increase the general robustness of drug effect. Lower frequency of skin treatment, which ensures adequate biological response, is a result of this. Topical corticosteroid delivery with very deformable vesicles, Transfersomes, thus improves the therapeutic risk-benefit ratio, arguably due to better targeting into and longer drug presence in the skin.
The influence of liposome composition, size, lamellarity and charge on the (trans)dermal delivery of tretinoin (TRA) was studied. For this purpose we studied both multilamellar (MLV) or unilamellar (UV) liposomes. Positively or negatively charged liposomes were obtained using either hydrogenated (Phospholipon90H) or non-hydrogenated soy phosphatidylcholine (Phospholipon90) and cholesterol, in combination with stearylamine or dicetylphosphate. Liposomal formulations were characterized by transmission electron microscopy (TEM) and optical and light polarized microscopy for vesicle formation and morphology, and by dynamic laser light scattering for size distribution. In order to obtain more information about the stability and the thermodynamic activity of the liposomal tretinoin, TRA diffusion through a lipophilic membrane was investigated. The effect of the vesicular incorporation of tretinoin on its accumulation into the newborn pig skin was also studied. The experiments were performed in vitro using Franz cells in occlusive conditions and were compared to three different controls. The tretinoin amount delivered through and accumulated in the several skin layers was detected by HPLC. Furthermore, TEM in combination with osmium tetroxide was used to visualize the skin structure after the liposomal administration. Overall obtained results showed that liposomes may be an interesting carrier for tretinoin in skin disease treatment, when appropriate formulations are used. In particular, negatively charged liposomes strongly improved newborn pig skin hydration and TRA retention, though no evidence of intact vesicle penetration was found.
To develop a more effective transdermal delivery method for lipophilic functional cosmetic compounds such as retinol, we formulated various deformable liposomes and compared their transdermal delivery efficiency with those of neutral or negatively-charged conventional liposomes. We tested the deformability of liposomes containing edge activators such as bile salts, polyoxyethylene esters and polyoxyethylene ethers. As indicators of deformability, we used the passed volume and phospholipid ratios during extrusion, as well as the deformability index. We found that the type of edge activator significantly affected the extent of deformability, and that Tween 20 provided the highest level of deformability. Accordingly, we used Tween 20 to formulate deformable liposomes containing retinol in the membrane bilayers, and conducted a skin permeation study in Franz diffusion cells, using dermatomed human skin and three-dimensional human keratinocyte layers. As compared with the use of conventional neutral or negatively-charged liposomes, the use of Tween 20-based deformable liposomes significantly increased the skin permeation of retinol. These results suggested that deformable liposomes might be of potential use for the formulation of retinol and other lipophilic functional cosmetic compounds.
Melatonin (MT) is a good candidate for transdermal delivery considering its short biological half-life, low molecular weight and a variable oral absorption. The objective of this work was to develop a novel formulation of melatonin for its efficient transdermal delivery. Melatonin loaded elastic liposomal formulation was prepared, characterized and the effect of this developed formulation on the in vitro permeation of melatonin across human cadaver skin was investigated, using a locally fabricated Franz diffusion cell. Skin permeation potential of the developed formulation was assessed using confocal laser scanning microscopy (CLSM), which revealed an enhanced permeation of the formulation to the deeper layers of the skin (up to 180 microm) following channel like pathways. Skin permeation profile of melatonin through elastic liposomal formulations was observed and the investigations revealed an enhanced transdermal flux (51.2+/-2.21 microg/cm(2)/h), decreased lag time (1.1h) and an optimum permeability coefficient (15.06+/-0.52 cm/h) for melatonin. The obtained flux was nearly 5 and 12.3 times higher than conventional liposomal and plain drug solution, respectively (P<0.005). Our result suggests the feasibility of elastic liposomal system for transdermal delivery of melatonin thereby eliminating the limitations of long lag time and poor skin permeation associated with the drug.
Microemulsions are clear, stable, isotropic mixtures of oil, water, and surfactant, frequently in combination with a cosurfactant. Microemulsions have been intensively studied during the last decades by many scientists and technologists because of their great potential in many food and pharmaceutical applications. The use of microemulsions is advantageous not only due to the facile and low cost preparation, but also because of the improved bioavailability. The increased absorption of drugs in topical applications is attributed to enhancement of penetration through the skin by the carrier. Saturated and unsaturated fatty acids serving as an oil phase are frequently used as penetration enhancers. The most popular enhancer is oleic acid. Other permeation enhancers commonly used in transdermal formulations are isopropyl myristate, isopropyl palmitate, triacetin, isostearylic isostearate, R(+)-limonene and medium chain triglycerides. The most popular among the enhancing permeability surfactants are phospholipids that have been shown to enhance drug permeation in a different mode. l-alpha-phosphatidylcholine from egg yolk, l-alpha-phosphatidylcholine 60%, from soybean and dioleylphosphatidyl ethanolamine which are in a fluid state may diffuse into the stratum corneum and enhance dermal and transdermal drug penetration, while distearoylphosphatidyl choline which is in a gel-state has no such capability. Other very commonly used surfactants are Tween 20, Tween 80, Span 20, Azone, Plurol Isostearique and Plurol Oleique. As cosurfactants commonly serve short-chain alkanols such as ethanol and propylene glycol. Long-chain alcohols, especially 1-butanol, are known for their enhancing activity as well. Decanol was found to be an optimum enhancer among other saturated fatty alcohols that were examined (from octanol to myristyl alcohol). Many enhancers are concentration-dependent; therefore, optimal concentration for effective promotion should be determined. The delivery rate is dependent on the type of the drug, the structure and ingredients of the carrier, and on the character of the membrane in use. Each formulation should be examined very carefully, because every membrane alters the mechanism of penetration and can turn an enhancer to a retarder. Various potential mechanisms to enhance drug penetration through the skin include directly affecting the skin and modifying the formulation so the partition, diffusion, or solubility is altered. The combination of several enhancement techniques such as the use of iontophoresis with fatty acids leads to synergetic drug penetration and to decrease in skin toxicity. Selected studies of various microemulsions containing certain drugs including retinoic acid, 5-fluorouracil, triptolide, ascorbic acid, diclofenac, lidocaine, and prilocaine hydrochloride in transdermal formulations are presented in this review. In conclusion, microemulsions were found as an effective vehicle of the solubilization of certain drugs and as protecting medium for the entrapped of drugs from degradation, hydrolysis, and oxidation. It can also provide prolonged release of the drug and prevent irritation despite the toxicity of the drug. Yet, in spite of all the advantages the present formulations lack several key important characteristics such as cosmetic-permitted surfactants, free dilution in water capabilities, stability in the digestive tracts and sufficient solubilization capacity.
To study influential factor on the microemulsion formulation for the delivery of a combination of Tanshiones and Salvianlic acids.
Area of oil-in-water microemulsion was investigated through pseudo-ternary phase diagrams that evalued the influence of different oliphase, Km-value and waterphase. Viscosity of microemulsions was measured to investigate the influence of oliphase and waterphase carrying different dose drugs respectively. Polydispersity index, intensity mean, volum mean and number mean of microemulsion particles were detected to value the particles diameter and their disposition.
Different oliphase, K.-value and waterphase had noticeable influence on the area of microemulsions and formulation composed of ethyl oleate, Solutrol HS15-EtOH (8 : 2), and the solution of Salvianolic acids, was the best one Viscosity of microemulsions was slightly influenced by oliphase and waterphase carrying different dose drugs respectively, but significantly influenced by the ratio of waterphase. The particles diameter and their disposition were also influenced by the ratio of waterphase. When the ratio of waterphase was not less than 87.5%, the particles were well-distributed and very stable.
The formulation is composed of ethyl oleate, Solutrol HS15-EtOH (8 : 2), and water can be used to delive the combination of Tanshiones and Salvianolic acids.