Lecithin-based nanostructured gels for skin delivery: an update on state of art and recent applications.

COREL-07039; No of Pages 15 Journal of Controlled Release xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Journal of Controlled Release journal homepage: www.elsevier.com/locate/jconrel

Review

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Yosra S.R. Elnaggar a,⁎, Wessam M. El-Refaie b, Magda A. El-Massik b, Ossama Y. Abdallah a

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Article history: Received 4 December 2013 Accepted 6 February 2014 Available online xxxx

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Keywords: Microemulsion Liposomes Nanogel Phospholipids Skin Permeation

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a b s t r a c t

Conventional carriers for skin delivery encounter obstacles of drug leakage, scanty permeation and low entrapment efﬁciency. Phospholipid nanogels have recently been recognized as prominent delivery systems to circumvent such obstacles and impart easier application. The current review provides an overview on different types of lecithin nanostructured gels, with particular emphasis on liposomal versus microemulsion gelled systems. Liposomal gels investigated encompassed classic liposomal hydrogel, modiﬁed liposomal gels (e.g. Transferosomal, Ethosomal, Pro-liposomal and Phytosomal gels), Microgel in liposomes (M-i-L) and Vesicular phospholipid gel (VPG). Microemulsion gelled systems encompassed Lecithin microemulsion-based organogels (LMBGs), Pluronic lecithin organogels (PLOs) and Lecithin-stabilized microemulsion-based hydrogels. All systems were reviewed regarding matrix composition, state of art, characterization and updated applications. Different classes of lecithin nanogels exhibited crucial impact on transdermal delivery regarding drug permeation, drug loading and stability aspects. Future perspectives of this theme issue are discussed based on current laboratory studies. © 2014 Published by Elsevier B.V. All rights reserved.

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Introduction . . . . . . . . . . . . . . . . . . . . . Liposomal gel . . . . . . . . . . . . . . . . . . . . 2.1. Classic liposomal hydrogels . . . . . . . . . . . 2.2. Modiﬁed liposomal gels . . . . . . . . . . . . 2.2.1. Transferosomal gels . . . . . . . . . . 2.2.2. Ethosomal gels . . . . . . . . . . . . 2.2.3. Proliposomal gels . . . . . . . . . . . 2.2.4. Phytosomal gels . . . . . . . . . . . . 2.3. Vesicular phospholipid gels (VPGs) . . . . . . . 2.3.1. Preparation methods . . . . . . . . . 2.3.2. Applications of VPGs for drug delivery . . 2.4. Microgel in liposomes (M-i-L) . . . . . . . . . . Lecithin microemulsion gels . . . . . . . . . . . . . . 3.1. Lecithin microemulsion-based organogels (LMBGs) 3.1.1. Pluronic lecithin organogels (PLOs) . . . 3.2. Lecithin-stabilized microemulsion-based hydrogels 3.3. Topical applications of lecithin microemulsion gels Characterization of phospholipid-based gel systems . . . 4.1. Morphological characteristics . . . . . . . . . . 4.2. Rheological behavior . . . . . . . . . . . . . . 4.3. In-vitro release/permeation testing . . . . . . .

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Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt Department of Pharmaceutics, Faculty of Pharmacy and Drug Manufacturing, Pharos University in Alexandria, Alexandria, Egypt

Lecithin-based nanostructured gels for skin delivery: An update on state of art and recent applications

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⁎ Corresponding author at: Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, 1 Khartoum Square, Azarita, Messalla Post Ofﬁce, P.O.Box 21521, Alexandria, Egypt. Tel.: +20 1147591065; fax: +20 3 4873273. E-mail address: [emailprotected] (Y.S.R. Elnaggar).

Please cite this article as: Y.S.R. Elnaggar, et al., Lecithin-based nanostructured gels for skin delivery: An update on state of art and recent applications, J. Control. Release (2014), http://dx.doi.org/10.1016/j.jconrel.2014.02.004

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5. Conclusion and future perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Topical application of conventional liposomes suffers from rapid drug leakage upon administration and accordingly a short residence time on the skin. In addition, the drug may leak from the prepared liposomes during storage by diffusion and erosion into the surrounding dispersion buffer [15]. Great efforts have been exerted in order to incorporate these liposomes into a gel structure to avoid their shortcomings [17,18,20,21]. Liposomes were found to be compatible with polymeric gelling agents derived from cross linked poly acrylic acid such as carbopol, hydroxyethyl-cellulose, and methyl cellulose [22,23]. Most commonly used as gellator is carbopol with concentrations ranging from 1 to 2% [20,21,24,25]. Many researchers have evaluated the prepared liposomal gels by comparing them to conventional gels or creams (containing the free drug) and neglected their comparison to the liquid state liposomes. They found that liposomal gels enhanced the skin retention of drugs, however, they did not enhance their systemic absorption [26–28]. These studies did not consider the effect of the gel matrix, but attributed the results to the liposome effect that is well known to provide a localized and controlled drug delivery when topically applied [17,28,29]. Recently, the release rates of lidocaine HCl [20] and diclofenac sodium [30] from liposome gel systems were evaluated compared to the aqueous liposomal dispersion The results revealed that incorporation of liposomes into gel form retarded the drug release compared to liposomal suspensions. Thus, it was concluded that the gel matrix viscosity may be responsible for the lower release rate from liposome gels and slower drug penetration [30]. Surveying the literature, different types of liposomal gels were observed. They can be classiﬁed according to their composition and

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2. Liposomal gel

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In the last decade, drug delivery via the skin has captured higher attention in order to minimize and avoid the limitations of traditional routes of administration. The major challenge in designing dermal or transdermal drug delivery systems is to overcome the natural transport barrier of the skin represented by the stratum corneum. To passively diffuse through the skin, drugs should have speciﬁc physicochemical properties. Although their boundaries are not well deﬁned it is generally accepted that the best drug candidates for passive transdermal diffusion should be nonionic, of molecular weight less than 400 or 500 Da, have adequate solubility in oil and water, partition co-efﬁcient (log Po/w) in the range of 1 to 3 or 4, a melting point less than 200 °C, and are of small dose (less than 50 mg per day, and ideally less than 10 mg per day) [1,2]. Other factors that must be also well considered include skin irritancy, short drug half life, and insufﬁcient bioavailability as they may hinder the development of transdermal delivery. Therefore, the transdermal route of administration cannot be employed for a large number of drugs and there is a need for using carriers that deliver the drug through the skin irrespective of its physicochemical characteristics. Accordingly, various delivery systems and strategies have been developed. Most promising are the lipid based systems including, vesicular systems [3], lipid microspheres [4], lipid nanoparticles [5], and microemulsions [6]. Among different types of lipid based systems, phospholipid (Lecithin) based nanocarriers were found intriguing. Phospholipids (PL) are natural, biocompatible molecules. In presence of water, they can form different supramolecular structures that can be modiﬁed sometimes by using some polymeric substances and solvents or by applying other methods to modulate topical drug delivery [7]. Owing to their similarity to biomembrane composition (Fig. 1), phospholipids are recognized as non-allergic, bio-friendly permeation enhancers. The amphiphilic nature of PL gathers the beneﬁts of aqueous and fatty vehicles in skin delivery while circumventing drawbacks against both. The most common phospholipid based nanoplatforms in this area are liposomes [8,9] and more recently lecithin microemulsions [10]. Liposomes – the traditional phospholipid-based vesicles – have been widely used as safe and effective drug vehicles in topical treatment of diseases, especially in dermatology, due to their proved potential in improving skin penetration and clinical efﬁcacy of several drugs [11,12]. They are able to incorporate a variety of hydrophilic and hydrophobic drugs, enhance the accumulation of the drug at the administration site and reduce side effects. Modiﬁed liposomes such as transfersomes and ethosomes have also been utilized to impart

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deeper permeation compared to traditional liposomes [13]. On the other hand, Lecithin microemulsions were found to have some advantages over liposomes, such as easier and lower cost preparation, absence of organic solvents and intensive sonication, and higher storage stability. These advantages may be due to the thermodynamic stability of microemulsions, thus they can spontaneously be formed by mixing an aqueous phase and a lipophilic phase together with a surfactant/cosurfactant mixture [14]. Nevertheless, topical application of lecithin based nanocarriers is hampered by their liquid status. They suffer from low contact time with the skin in addition to drug leakage upon application and storage [15,16]. Incorporation of such nanocarriers into gel matrices is then anticipated to circumvent drawbacks of liquid status upon skin application [16–18]. Moreover, entrapment of such systems inside polymer matrices offers an opportunity to additionally modify the drug release kinetics. Additionally, for liposomal dispersions – that are well known to be unstable and aggregated by time – gelling of the system will improve their stability [19]. Recent years of research have witnessed the emergence of various types and generations of lecithin based nanostructured gels. The large diversity in matrix composition, technologies, developing materials and mechanisms of these systems highlighted the need for a comprehensive overview about them. This review is the ﬁrst one to focus on gelation of lecithin based nanocarriers compared to their liquid state and conventional topical vehicles. An emphasis on different types of liposomal gels in contrast to lecithin microemulsion gels would be addressed. Differences would be highlighted in view of state of art, matrix composition, morphology, preparation methods, applications and assessment. Future perspectives of these vehicles would be discussed as well.

1. Introduction

Fig. 1. Chemical structure of phospholipid molecules.

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Fig. 2. Formation of liposomal hydrogels.

2.2. Modiﬁed liposomal gels

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Recently, it was proved that conventional liposomes are of little value as carriers for transdermal delivery, as they do not deeply penetrate the skin [33]. They were found to remain conﬁned to the upper layers of the stratum corneum. Confocal microscopy studies showed that intact liposomes were not able to penetrate into the granular layers of the epidermis [34]. In addition, aqueous dispersions of vesicular systems may have a limited shelf life due to aggregation, fusion, leaking or hydrolysis of entrapped drugs [3]. One of the major advances in vesicle research was the preparation of vesicles with modiﬁed properties allowing them to successfully deliver drugs in deeper layers of the skin (such as transfersomes and ethosomes) and to improve the vesicle stability (e.g. pro-vesicle and phytosomes).

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2.2.1. Transferosomal gels Transfersomes are ultra-deformable hydrophilic lipid vesicles loaded with an active substance and applied to the skin in an aqueous formulation. They consist of phospholipids and an edge activator which is generally a single chain surfactant with a high radius of curvature. Edge activators are responsible for weakening the vesicles' lipid bilayers increasing their ﬂexibility and deformability allowing them to be

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Liposomal hydrogels can be prepared either by incorporation of the prepared liposomes, after separation of the un-entrapped drug, into suitable gel matrix [21,23,31] or by adding gelling agents in liposome dispersions without separation of un-entrapped drug (Fig. 2) [20,32]. The later method obviates the need forcomplex separation steps and prevents drug loss, offering very high encapsulation efﬁciency for the system.

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squeezed through pores of the stratum corneum (Fig. 3) [35]. Sodium cholate, sodium deoxycholate, Span 60, Span 65, Span 80, Tween 20, Tween 60, Tween 80 or dipotassium glycyrrhizinate are commonly used as edge activators [35,36]. Transfersomes are supposed to cross the skin under the inﬂuence of a transepidermal water activity gradient which is considered the driving force for vesicle penetration through the skin [37]. When transfersomes come in contact with the skin, evaporation of the water content of the preparation starts depriving vesicles of their suspending medium. Transfersome vesicles have a tendency to evade a dry environment (xerophobia). Thus, they are attracted by the higher water content layers of the skin, resulting in spontaneous migration of the drug-loaded vesicles through the skin barrier Fig. 3[37]. However, other studies gainsaid the hypothesis that intact transfersomes could penetrate the skin without fragmentation or loss of integrity. They agreed with transfersome penetration enhancing effect on different drugs but proposed another mechanism for this enhancement. They attributed that penetration enhancement to the particular exogenous amphiphiles emerging from these vesicles that might interact with the tissue barrier and facilitate drug penetration [38]. Fig. 3 Similar to aqueous liposomal dispersions, transferosome liquid preparations suffer rapid leakage at the application site. Therefore, incorporation of transfersomes into gel matrices was investigated to circumvent such drawback. Some transferosomal gels were prepared and evaluated for their dermal and transdermal delivery of drugs such as ketoprofen [39], insulin [40], and diltiazem HCl [41]. Ketoprofen in transferosomal gel (Diractin®) is a relatively new, carrier-based formulation for local application which was found to relieve knee osteoarthritis pain comparable to oral celecoxib [42]. In muscle biopsy studies conducted in pigs, Diractin® showed substantially higher drug concentration in muscles, as compared to conventional topical products and oral ketoprofen, [43]. Insulin, as a large peptide, cannot permeate easily through the skin. Being expensive and of low physical stability, it is very difﬁcult to improve the transport efﬁciency by increasing insulin concentration. Tranfersomal drug delivery system may be a better alternative for

preparation methods into liposomal hydrogels, modiﬁed liposomal gels, vesicular phospholipid gels (VPG), and microgel in liposomes (M-i-L).

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Fig. 3. Scheme of the skin structure and transfersome penetration mechanism. a) A sketch of the skin structure showing SC: stratum corneum, SS: stratum spinosum, SB: stratum basale, and D: dermis. b) Mechanism of transfersome penetration through the skin.

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2.2.2. Ethosomal gels Ethosomes are soft lipid vesicles containing phospholipids, alcohol (ethanol and isopropyl alcohol) in relatively high concentration (20–45%) and water. Better skin permeability observed for ethosomes is attributed mainly to their high ethanol concentration. Ethanol is an established permeation enhancer and is proposed to ﬂuidize the ethosomal lipids and stratum corneum bilayer thus allowing the soft, malleable vesicles to penetrate the disorganized lipid bilayer [33,44]. Although containing high alcohol concentration, ethosomes were studied for their effect on the skin and were found to be non irritant following 12, 24, and 48 h application [45]. Gel containing ethosomal vesicles of aceclofenac were prepared and evaluated compared to gel containing the free drug and the marketed gel formulation. Enhancement of aceclofenac transport across the skin, when using ethosomal gels, was observed in terms of higher in-vitro drug release and in-vivo activity [25]. Drug release from ethosomal dispersion was higher than from gel incorporating ethosomal vesicles, which may be due to the viscosity of the gel [46]. Ethosomes were also compared to liposomes and transfersomes in some studies and were found to be superior in enhancing skin penetration and drug accumulation in the skin [47,48].

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2.2.4. Phytosomal gels Phytoconstituents are mostly water-soluble molecules (e.g. phenolics, glycosides, and ﬂavonoids). Thus their effectiveness is limited because they are poorly absorbed when they are applied topically or taken orally [51]. Complexing these botanicals with phospholipids was found to greatly enhance their bioavailability with faster and improved absorption through the skin [52]. Phytosomes and liposomes are totally different in their structures (Fig. 4). Liposomes are prepared by simply mixing the water soluble drug and phosphatidylcholine molecules with no chemical bond formation. There are a huge number of phosphatidylcholine molecules surrounding a small amount of the water-soluble compound. Phytosomes, by contrast, depend on complex formation via hydrogen bonding between the SPC polar head and the polar functionalities of the substrate [52]. This complex may be of 1:1 or 2:1 ratio depending on the substance. Thus each one or two phosphatidyl choline molecules will be attached to one drug molecule [52]. Phytosomes are much better absorbed than liposomes because of this difference in structure [53]. In a recent study, vesicles of boswellic acid were developed by complexation with phosphatidylcholine and showed a notable increase in absorption and anti-inﬂammatory activity of boswellic acid through the skin [54]. Phytosomal gel bearing poorly absorbable curcumin was recently prepared in order to improve its topical bioavailability [55]. The system showed superiority in antioxidant, anti-aging, and antiwrinkle effects when compared to plain curcumin gel, liposomal and niosomal gels, and physical mixture of curcumin with phosphatidylcholine [55]. The most recent liposomal gels, their matrix composition and applications are presented in Table 1.

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2.2.3. Proliposomal gels The major problem in the development of vesicular systems at industrial and clinical levels is their poor stability. Proliposomes offer a versatile delivery concept for improving the stability and allowing easier sterilization on large scale[49]. This approach was used in order to increase the stability of liposomes, niosomes, and extended to deformable liposomes [3,33]. Proliposomal formulations were prepared by applying conventional liposome preparation methods and using a water soluble carrier to convert the system into a dry free ﬂowing powder. The dry powder was further converted to gel form by incorporation into a suitable structured vehicle. Recently, prednisolone proliposomal gel was formulated and evaluated for effective topical pharmacotherapy in treatment of rheumatoid arthritis [24]. Results showed that the proposed proliposomal gel gave a sustained drug release with enhanced anti inﬂammatory activity suggesting its potential in effective treatment of rheumatoid arthritis [24]. The provesicular approach has been extended to transfersomes and a liquid crystalline protransfersome gel was prepared for transdermal delivery of the contraceptive agent, levonorgestrel [50]. The proposed protransfersome gel is a liquid crystalline gel in which the drug is intercalated within phospholipids. The protransfersomes incorporated inside the gel were designed to be converted into transfersomes in situ by absorbing water. The system was evaluated in vitro and in vivo

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by different tests. The optimized protransfersome gel formulation enhanced the in vitro skin permeation ﬂux 15.82 ± 0.37 μg/cm2/h, as compared to 0.032 ± 0.01 μg/cm 2 /h for plain drug solution. Protransfersome gel also showed good stability and there was no change in liquid crystalline nature, drug content, and other characteristic parameters after storage for 2 months. A single topical application of the gel formulation achieved 0.139 ± 0.05 μg/mL peak plasma concentration of levonorgestrel within 4 h which was maintained up to48 h. In vivo performance of the protransfersome gel formulation showed increase in the therapeutic efﬁcacy of the drug. It was concluded that the optimized protransferosomal formulation of levonorgestrel had better skin permeation potential, sustained release characteristic, and better stability than proliposomal formulation [50].

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the conventional insulin therapy. In a recent study [40], insulin in transferosomal gel showed good permeation results with in vitro permeation ﬂux of 13.50 ± 0.22 μg/cm2/h through porcine ear skin. In addition, further improvement of skin permeation was observed by application of iontophoresis with in vitro skin permeation ﬂux of 17.60 ± 0.03 μg/cm2/h. The in vivo study of optimized transferosomal gel has demonstrated prolonged hypoglycemic effect in alloxan-induced diabetic rats over 24 h after transdermal administration. This study revealed that, the developed and optimized insulin containing transferosmal gel can be transdermally administered in the treatment of insulin dependent diabetes mellitus with maintaining lower blood glucose level and improved patient compliance [40]. In another recent study [41], the antihypertensive drug diltiazem HCl was formulated in transfersomes which were then incorporated in a gel matrix. Results showed that diltiazem HCl permeated through rat skin showed three- to four-fold higher sustained effect using gel incorporating transfersomes compared to those from plain drug gel. These results suggest that gel incorporating transfersomes may be of value for the transdermal delivery of diltiazem hydrochloride in the treatment of hypertension.

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Fig. 4. Diagrammatic composition of phytosomes versus liposomes.

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Table 1 Recent applications of different types of liposomal gels for topical drug delivery.

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Gel type

Matrix composition

Active agent

Outcome

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Liposomal gel

PC in carbopol 934 gel base

Tretinoin

Liposomal gel Ethosomal gel Transferosomal gel Elastic liposomal (EL) gel Liposomal hydrogel

(PC, cholesterol) Diclofenac (PC, ethanol 20–40%) sodium (PC, cholesterol, span 80) incorporated into 1% carbopol 914 gel.

1. Reduced drug leakage compared to that of liposomal dispersion [18] 2. Prolongation of drug diffusion and increase in skin drug retention after liposomal encapsulation Transfersomes and ethosomes provided higher permeation and residual [64] drug concentration compared to liposomes and conventional gel.

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(Phospholipon® 90 G and Tween 80/Span 80) embeddedin carbopol 934 or 940

Neomycin sulfate (NS)

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Liposomal gel

(Lecithin, cholesterol) embedded in carbopol included PEG-400, Lidocaine azone, poloxamer, and propylene glycol hydrochloride (LDH), (Soya lecithin, cholesterol) in 1% carbopol 934 Selegiline

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Liposomal gel

(Soya lecithin, cholesterol) in carbopol 934

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Proliposomal gel (Mannitol (carrier powder), lecithin and cholesterol) in carbopol gel Ethosomal gel (Soyabean lecithin, ethanol, propylene glycol) in carbopol gel

Transferosomal gel

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Transferosomal gel Liposomal hydrogel Liposomal gel

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(Soya lecithin, cholesterol,tween 80 and sodium deoxycholate, dimethyl sulfoxide (DMSO)) embedded in methyl cellulose gel base Soybean lecithin (PC), Tween 80, Sodium cholate, and Sodium deoxycholate (Lipoid S-75 or Lipoid S-100) in carbomer hydrogel Soy lecithin and cholesterol) in carbopol gel

[66] [24] [25]

[39] [50] [20] [40]

Temoporﬁn (mTHPC) Caffeine

The optimized formulation delivered high amounts of mTHPC to the SC [67] and deeper skin layers, and it possessed desirable rheological properties. Increase skin permeation and deposition, reduction of cellulite deposits [68] over human body

2.3. Vesicular phospholipid gels (VPGs)

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Vesicular phospholipid gels (VPGs) are semisolid, aqueous phospholipid-dispersions, in which vesicles or liposomes represent the lipid phase as described by Brandl et al. [56,57]. VPGs acquire their gel like structure from the tightly packed arrangement of the vesicles unlike liposome hydrogels in which hydrophilic polymers are added to the liposomal dispersion to provide the gel structure (Fig. 5). The densely packed arrangement of the numerous vesicles in VPGs minimizes the inter-vesicular aqueous spaces giving rise to steric

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[21]

More sustained effect compared to that from plain drug gel.

PC: phosphatidyl choline; EL: elastic liposomes; PTG: protransferosomal gel; Ch: cholesterol;SC: stratum corneum.

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[17]

Diltiazem HCl

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[65]

[41]

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Transfersome® gel Protransfersome PC + Ch:alcohol:aqueous phase, 5:4:5 wt/wt gel (PTG) Liposomal gel (Soya lecithin and cholesterol) in carbopol gel base

t1:16

Improved bioavailability, maximum therapeutic effect, and sustained release of drug. Ketoconazole Greater permeation, maximum antifungal activity, and much slower release compared to plain gel and cream. Prednisolone Sustained release with enhanced anti inﬂammatory activity. Superior stability when compared to traditional liposomes. Aceclofenac. A signiﬁcantly higher permeation rate and in-vivo efﬁciency of Aceclofenac compared to marketed Aceclofenac gel and the gel containing free drug. Ketoprofen Ketoprofen in Diractin was signiﬁcantly superior in pain relief to placebo and to oral ketoprofen. Levonorgestrel. Higher entrapment efﬁciency, skin permeation potential, and stability than proliposomal formulation. Lidocaine High % of encapsulated drug and prolonged release rate compared to hydrochloride conventional formulations. Insulin Good permeation results and prolonged hypoglycemic effect.

t1:15

EL enhanced NS penetration and deposition. EL gel showed superior stability compared to its corresponding suspension. Enhanced LDH percutaneous permeation rate compared with conventional gel.

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Ref.

Fig. 5. Diagrammatic comparison between (a) vesicular phospholipid gels and (b) liposomal suspension.

interactions between neighbor-vesicles and consequently gel-like consistency [58]. In conventional liposomes, only the aqueous compartments inside the vesicles act as drug reservoirs; resulting in low entrapment efﬁciency of hydrophilic compounds. Additionally, the entrapped drug is rapidly leaked from phospholipid membrane by diffusion and erosion into the surrounding dispersion buffer resulting in insufﬁcient retention [59]. Moreover, liposome processing methods often involve conditions that might become an issue for protein drugs (induce denaturation and/or aggregation) [60]. VPGs have been shown to be advantageous compared to conventional liposomal formulations. They have the ability to increase the encapsulation efﬁciency by the localization of the drug, that is not encapsulated inside liposomes during the preparation, inbetween the vesicles of the phospholipid matrix retaining it inside the gel. Drug leakage during storage is minimized in VPGs due to the constant ratio of encapsulated to free drug leading to an increased shelflife compared to conventional liposomal formulations as shown for VPG formulations with the anticancer drugs gemcitabine [61], vincristin [62], and 5-Fluorouracil [63] and protein drugs [15]. Furthermore, VPG manufacturing processes are simple, easy to upscale, and avoid the use of organic solvents preserving protein stability and safety [15].

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2.3.1. Preparation methods Two main methods were described in the literature for the preparation of VPGs, high-pressure homogenization [69] and recently dual asymmetric centrifugation [70].

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2.3.2. Applications of VPGs for drug delivery Although offering a lot of advantages over conventional liposomes regarding preparation, encapsulation, and storage stability, VPGs were not studied so far for their efﬁciency in delivering drugs dermally or transdermally. VPGs have been widely used as intermediates for liposome preparation and as semisolid local depot formulations for sustained release of drugs upon implantation or injection, and to a lesser extent used as a tool for absorbability screening.

Local depot systems for drugs sustained release. Local delivery is preferred to provide locally high drug concentrations. VPGs offer potential as local depot systems as they appeared to retain entrapped drugs when in contact with excess aqueous medium [74,75]. The potential of undiluted VPGs as implants to act as depot system for sustained drug release was examined for various low molecular weight drugs, especially in the ﬁeld of anticancers [61,62], small peptide hormones [76], and recently protein drugs [15]. A very important achievement has recently occurred when Tian et al. succeeded in encapsulating erythropoietin, a relevant therapeutic protein by dual asymmetric centrifugation in vesicular phospholipid matrices without protein destabilization [15]. Furthermore, the VPG enables sustained protein release which occurs in a linear manner without any burst effect. This is a particular advantage for indications that require constant drug levels over prolonged time periods [15].

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2.4. Microgel in liposomes (M-i-L)

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This technology is the latest one in liposomal gels that has not so far been employed in dermal drug delivery. Lipobeads [80], liposomenanogel assembly [81], gel core liposomes [82], microgel in liposomes (M-i-L) [83], and hydrogel supported lipid bilayer [84] are different terminology utilized in the literature to describe this type of liposomal gels. M-i-L is a phospholipid bilayered vesicle incorporating hydrogel polymer inside its core. Thus, it combines the advantages of both compartments in addition to mimicking the natural cell structures. Moreover, the incorporated polymer network of the inner microgel supports the lipid bilayer preventing their rapid degradation inside the human body and early drug release. The biomimicry with viruses and cells makes gel-core liposomes an ideal tool for the activation of the desired types of humoral and cell immunity. They were prepared and utilized intramuscularly and intranasally in different studies as an effective tool for immunization and showed promising results [32,82]. Different approaches are adopted for the preparation of M-i-L. The ﬁrst is to prepare the microgel then coating it with the phospholipid bilayer. This can be done either by mechanical adsorption of lipids onto gel particles [85] or electrostatic adsorption simply by mixing oppositely charged liposomes and hydrogels (Fig. 6)[84]. Anchoring lipid molecules to the surface of the hydrogel is also utilized for coating hydrogels with liposomes [80]. Anchoring can be done by covalently attaching fatty acids to the hydrogel surface. This is then added to liposomal suspension where fatty acid hydrophobic chains spontaneously form a lipid bilayer shell around the hydrogel particles [80] (Fig. 7). Although this anchoring technique is commonly used and form gel-core liposomes

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Fig. 6. Coating hydrogels with liposomes by electrostatic adsorption.

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Dual asymmetric centrifuge (DAC). DAC technology has been known for the rapid mixing of viscous components [72,73]. This technique is applied recently for production of VPGs besides high pressure homogenization. Rotation of the sample around two axes, a central axis and a second one in the center of the sample container, is the main principle of this technique. The combination of these two contra-rotating movements efﬁciently homogenizes viscous materials. Some studies used glass beads for homogenization during centrifugation process [70]. However, other studies omitted the use of glass beads as they may lead to temperature increase and protein loss due to adsorption onto the glass beads [15]. In contrast to high pressure homogenization, small vesicles can be obtained from VPGs processed using DAC for longer periods. This may indicate that DAC generated a milder shear force compared to high pressure homogenizer, which might be more applicable for entrapping sensitive compounds, e.g. proteins [15]. Moreover, short DAC runs can be applied with sample cooling after each thus, reducing the temperature to which the sample is exposed during processing [70]. On the other hand, VPGs prepared by DAC showed higher entrapment efﬁciency compared with those prepared by high pressure homogenization [70].

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Tools for absorbability screening. VPGs were utilized as a bilayer diffusion barrier for drug permeability screening. A tight barrier was prepared by depositing ﬁlter-extruded liposomes into the pores and onto the surface of a ﬁlter support with subsequent solvent evaporation and freeze-thaw cycles [77]. The measured apparent permeability values for different drugs obtained from this VPG-model assumed to show good correlation with the obtained amount absorbed in vivo equally as Caco-2 model [77]. Although being easier and less expensive, this technique can be used only when the release is by passive diffusion mechanism. It cannot show the same results as Caco-2 cells when the release is not by passive diffusion as the effect of different binding proteins, enzymes or efﬂux transporters would not be assessed. Caco-2 cells are widely used in vitro model simulating small intestinal absorption. They originate from a colon carcinoma, spontaneously differentiate to cells resembling mature small intestinal enterocytes and express carrier proteins similar to those of the small intestine. Consequently, they can be used for the estimation of active transport processes during intestinal absorption [78,79].

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High pressure homogenization. High pressure homogenization is used for preparing VPGs of small and uniform vesicle sizes. The preparation approach is dependent on the one-step liposome preparation technique originally described by Brandl, in which no organic solvent is involved [56]. In this method, dry lipids are mixed with buffer or drug solution with gentle shaking. The formed lipid dispersions were processed with a high-pressure homogenizer to obtain ﬁnely dispersed lipid particles which swell instantaneously leading to the formation of small liposomes [69]. The morphology and size distribution of the liposomes depend on the applied mechanical stress, the number of homogenization cycles, and the lipid type and content [71].

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Precursors for liposomes. VPGs can be transformed into conventional liposome dispersions by mixing with excess aqueous medium and gentle agitation [69]. Redispersing the VPGs by manual shaking or using a ball mill was found to be appropriate. Liposomes prepared by this technique have small and uniform vesicle sizes, and improved storage stability [62], in addition to higher encapsulation efﬁciencies of hydrophilic compounds [61] compared with other liposome preparation techniques. Moreover, there is no need for the removal of un-encapsulated drug [62].

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The bicompartmental structure of gel-core liposomes allow for bifunctionalization of both the phospholipid bilayer shell and the hydrogel core. Therefore, these systems will have increasing application potential as they can be grafted internally and externally to enhance their permeation, targeting speciﬁcity, loading capacity, entrapment efﬁciency, stability, and environmental responsiveness to different triggering stimuli [81]. In general, the M-i-L design can be used for all known routes of drug delivery. Promising results were obtained in different studies examining the use of gel-core liposomes intramuscularly and intranasally [32,82] and more speciﬁcally for vaccine delivery. However, assessment of its potential for dermal application is still needed.

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According to the matrix structure, lecithin microemulsion gels can 497 be classiﬁed into two major classes. 498 499

LMBGs are thermodynamically stable, clear, viscoelastic, biocompatible, and isotropic phospholipid structured systems. These gel structured water in oil microemulsions were ﬁrst described by Scartazzini and Luisi in 1988 in a study investigating the suitable conditions for soy lecithin to form reverse micelles [86]. They observed an abrupt rise in the viscosity by the addition of minimal amounts of water into organic solutions of soy lecithin. The naturally occurring surfactant – lecithin – can form reverse micelle-based microemulsions in non polar environment because of its geometrical discipline. These small reverse micelles upon addition of a speciﬁc amount of water, likely grow monodimensionally into long ﬂexible and cylindrical giant micelles, above a critical concentration of lecithin. Then, these giant micelles form a continuous network that immobilizes the external organic phase forming a gel or jelly-like state [87]Fig. 8. These gel-like systems were called microemulsion-based gel or organogel; since the main component is organic solvent [86].

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with high quality, organic solvents are used in addition to multiple freezing and thawing cycles which make the process less compatible and tedious [84]. The other approach is to prepare liposomes, incorporating a polymerizable monomer of the polymer or the polymer in a sol form, simply by reverse phase evaporation technique. Cross linking and gellation of the core are then induced after removal of the unentrapped part of the polymer [32].

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Fig. 7. Mechanism of lipobead formation by anchoring.

Fig. 8. Steps of lecithin microemulsion-based organogel formation.

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Recently, oil in water microemulsions has been turned to gel in order to be more suitable for dermal applications. This was achieved by the addition of different water soluble polymers or hydrogel matrices such as gelatin, carbomer 934, carbopol, and carrageenan [16,95–97]. In this case, only the external water phase was gelled or thickened while the internal micoemulsion droplets were still liquid [98]. Lecithin- stabilized microemulsion-based hydrogels are typically water continuous microemulsions where lecithin is added as a surfactant to stabilize the system. Then they turned into gel state using one of the previously mentioned hydrogel matrices. However, lecithin

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3.1.1. Pluronic lecithin organogels (PLOs) The high purity grade of lecithin is expensive and difﬁcult to obtain in large quantities. Therefore, some studies tried to incorporate synthetic polymers (e.g., pluronics) in LMBGs, for their expediency as cosurfactants and stabilizers [93,94]. These studies showed possible organogelling with lecithin of relatively lesser purity by the inclusion of pluronics as cosurfactants. Pluronics are a series of nonionic, closely related block copolymers of ethylene oxide and propylene oxide. They are known also as poloxamers, poloxamer polyols, or lutrols. LMBGs containing pluronics have been termed as pluronic lecithin organogels (PLOs), poloxamer organogels, or pluronic organogels.

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Skin permeation and absorption of both lipophilic and hydrophilic drugs were found to be enhanced signiﬁcantly when incorporated inside lecithin microemulsion gel system. This enhanced transport may be attributed to the system's amphiphilicity; thus enabling high solubilization capacity, organized micellar structure, and ability to ﬂuidize skin membrane lipids providing effective permeation. In addition, histological examination of the skin showed no signs of toxicity even with prolonged use [105]. Furthermore, due to their occlusive nature, long term stability and spontaneous production, lecithin microemulsion gels acquired increased interest as a topical delivery vehicle especially for thermolabile drugs [92]. In a recent study, it was proved that lecithin organogels represent good vehicles for fenretinide, one of the less toxic analogs of vitamin A applied in the chemoprevention and in the treatment of different types of malignancies including skin tumors [106,107]. The drug was solubilized easily in the organogel matrix with no thermal stresses. Fenretinide diffusion from all the prepared organogel formulations was found to be at least 20 folds higher than from conventional topical forms. Moreover, fenretinide stability was maintained for almost 4 months [108]. Microemulsion based lecithin organogel formulations appeared also to be beneﬁcial for topical delivery of ﬂuconazole with an increase in the

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cannot be utilized as the sole surfactant to prepare microemulsions as it tends to form liquid crystalline phases [99]. Therefore, a cosurfactant should be used when formulating these microemulsions. Various medium chain alcohols such as pentanol [99] and isopropyl alcohol [97] were formerly used as co surfactants. However,due to the toxic effect of alcohols [100], researchers tend to formulate alcohol-free lecithin microemulsion hydrogels by using linker molecules [16,101]. Linkers are amphiphilic additives formed by hydrophilic linkers such as sodium octanoate, decaglycerol monocaprylate/caprate and PEG6-caprylic/capric glycerides, and lipophilic ones such as sorbitan monooleate. When added to lecithin, linker molecules tend to distribute themselves beside lecithin polar head (hydrophilic linkers) or beside its non-polar tail (lipophilic linkers) [102]. The addition of linkers will help lecithin to stabilize the microemulsions by increasing their interactions with the oil phase (lipophilic linkers) and with the aqueous phase (hydrophilic linkers). Moreover, combining both hydrophilic and lipophilic linkers will improve the solubilization capacity of the system by forming surfactant-like self-assemblies [103]. Lecithin-linker microemulsions are characterized by their lower toxicity and lower viscosity compared to alcohol containing lecithin microemulsions. In addition, they have characteristic small droplet size and high afﬁnity to penetrate epithelial tissues and to utilize these tissues as reservoir for drug delivery [101,104]. Viscosity of these systems was successfully increased by the addition of gelatin to form lecithin-linker microemulsion gelatin gels suitable for transdermal applications without spreading of the formulation beyond the intended area and with no effect on the drug release or remaining in the skin [16].

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Matrix composition: LMBG matrix consists of three main components, lecithin (a surfactant) as gelator molecules, a nonpolar organic solvent as external or continuous phase, and a polar agent, usually water. The transfer into jelly-like state has been demonstrated only for nonaqueous solutions of naturally occurring unsaturated lecithins with high degree of purity, containing at least 95% PC content [86,88]. Poorly puriﬁed lecithin does not possess gel-forming properties. A variety of organic solvents can be used to form gel in presence of lecithin. Among them, the fatty acid esters e.g., isopropyl myristate, isopropyl palmitate are of particular interest for topical applications of LMBGs. This has been attributed to their skin penetration enhancing property in addition to their biocompatible and biodegradable nature [89]. Water is the most commonly employed polar agent, although some other polar solvents such as glycerol, ethylene glycol, and formamide have also been found to possess the capability of transferring an initial non-viscous lecithin solution into a jelly-like state [90]. The polar agent has an essential role in the process of gelling, acting as a structure forming and stabilizing agent. The physicochemical properties of the used polar solvent affect greatly its gel-forming ability. Studies showed that gel-forming solvents should have high surface tension, polarity index, relative permittivity (dielectric constant), and a strong ability to form hydrogen bonding [90,91]. Recently, a new way was described in the literature for the formation of the long ﬂexible reverse micellar chains of LMBG without the addition of water. This was done by the use of bile salts that have a distinctive structure able to resemble the role of water in organogelling [92].

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Fig. 9. TEM images of a) liposomes (average size 546.4 nm ± 16.5 nm, PDI 0.317 ± 0.016); b) transfersomes (average size 483.2 nm ± 8.5 nm, PDI 0.256 ± 0.018) and c) ethosomes (average size 342.1 nm ± 1.5 nm, PDI 0.208 ± 0.013), bar = 800 nm.

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hydrophobic and hydrophilic drugs in high concentrations [105,108,109,115]. Therefore, they could be considered superior to liposomal gels in that regard. Liposomes are well documented to have small area for the incorporation of drugs thus they are able to entrap only low concentrations [116]. On the other hand, liposomal gels – especially modiﬁed ones – may be superior in their deep skin permeation and deposition properties allowing them to act as drug reservoirs inside the skin [13,41,43].

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drug solubility and antifungal activity. Moreover, the histopathological data of this study showed that the prepared lecithin organogels were safe enough for the topical purpose [109]. In another study, lecithin microemulsion gels were compared with hydrogels for the topical delivery of aceclofenac and were reported to be more effective and safer [110]. Fujii et al. [111] revealed that indomethacin permeation increased when incorporated into lecithin microemulsion gel compared to drug suspension. Lecithin microemulsion gels have been also examined as a matrix for topical delivery of a wide variety of therapeutic compounds with promising results, including NSAIDS, peptides, and amino acids [105,112]. Furthermore, they have also been found to be excellent carriers for macromolecule delivery; given the ability of these carrier systems to incorporate protein drugs [113]. Emphasizing the importance of lecithin microemulsion gel formulations, Phlojel® Ultra was produced. It is a marketed lecithin microemulsion gel product that is formulated for cosmetic properties then used as an attractive base for drug compounding. It is non-greasy and permeates the skin rapidly after topical application leaving no residue. It was found that the incorporation of an active ingredient inside this formulation resulted in enhancement of skin penetration and reduction of the amount of the drug needed [114]. No research study has so far compared topical drug delivery from both systems. Surveying the literature, it could be concluded that lecithin microemulsion gels were able to efﬁciently solubilize both

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Fig. 10. Lamellar liquid crystalline structure of protransferosomal gel (photomicrograph A, ×400), scale bar = 500 μm and vesicular structure of transfersomes formed upon hydration of PTG (photomicrograph B, ×1000). Scale bar = 1 μm.

Fig. 11. Electron micrograph of redispersed vesicular phospholipid gel showing the densely packed vesicles.

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In order to describe the different characteristics of these phospholipid structured gels, their morphological characteristics and inner structure have to be ﬁrst deliberated. In addition, any vehicle used for topical drug delivery should be studied for its rheological behavior. Furthermore, entrapment efﬁciency, skin permeation, and drug release must be tested with their controlling factors. It is worth repeating that there is no study differentiating between the above mentioned gel systems by the same characterization methods. Therefore, the aim of this part of the review is to pull together the different parameters and techniques used for characterization of these phospholipid-based gels and to differentiate between their morphological characteristics whenever possible.

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Detailed literature survey indicated that most studies done on liposomal hydrogels characterize the morphological characteristics of the prepared vesicles before their incorporation into the gel matrix [24,25,50,117]. Different microscopic techniques were used for the determination of vesicle shape and surface morphology including optical microscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM) [20,24,25,117]. Regarding the vesicle size, it has been mostly determined using dynamic light scattering techniques [50,118]. Going into the morphology of these abovementioned phospholipidbased gels, one can say that these systems are different in their morphology. Liposomal gels are vesicular in shape but there may be a difference between the different types of vesicles, i.e. liposomes may appear different from transfersomes and ethosomes. In a recent study [48], three selected liposomal formulations namely, liposomes, transfersomes, and ethosomes were examined by TEM (Fig. 9). Results demonstrated that, in all the examined formulations the required vesicle nano size was obtained. Vesicles of the liposomal formulation were poorly homogeneous in size and shape (Fig. 9a). Some reduction in vesicle mean size, and polydispersity were noticed for formulation of transfersomes containing Tween 80 (Fig. 9b). Ethosomes

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in very heterogeneous multilamellar vesicles while using high pressure homogenization produced pastes consisting mainly of homogenous small and unilamellar vesicles, as long as the lipid content was less than 450 mg/g (Fig. 12a)[74]. Nevertheless, lipid content greatly affected the characteristics of the vesicles within homogenized pastes. When higher lipid content was applied, large multilamellar vesicles, planar lamellar masses, besides small unilamellar vesicles were found resulting in more heterogeneous sizes extending to a range of several 10 μm (Fig. 12b)[74]. Gel-core liposomes were viewed by atomic force microscopy (AFM) very clearly and both the gel core and the bilayer shell were observed (Fig. 13a) [81]. Core gelling was also conﬁrmed by treating formulation with TritonX-100, a nonionic detergent able to dissolve the lipid bilayer. Treatment with triton-X100 showed different images for liposomes before and after core gelling. Spherical structure of gel core liposomes was maintained in the formulation treated with TritonX-100 after core gelling (Figs. 13b, 14a) [81] but before gelling of the core, the spherical structure was completely destroyed (Fig. 14b) [82]. This can be ascribed to the presence of the polymer in the sol form before gelling, thus it could not keep its spherical shape after lipid bilayer removal. On the other hand, the supramolecular structure of lecithin microemulsion gel is more complicated and totally different compared that of liposomes. Packing structure of lecithin organogel depends on the amount of water added as detailed in Fig. 15[120]. Lecithin microemulsion organogels appeared to have long, ﬂexible and worm-like tubular micellar structures Fig. 16[121]. It has been found that, the self associated supramolecules forming the interior structure of lecithin microemulsion gels resulted in relatively complicated characterization studies. Therefore, multiple instrumental techniques, based on microscopy, spectroscopic and scattering analysis, were required to be applied in parallel in order to fully characterize these systems. As mentioned previously, the isotropic nature and

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containing Tween 20 were found to be the most homogeneous and smallest nano-sized vesicles (Fig. 9c) [48]. However, it is very important to visualize vesicles when incorporated inside the gel to detect if the gelling process has any effect on the morphology of these phospholipid based carriers. This has been done in a study by evaluating morphology of samples of liposomal gels after being suitably diluted using optical microscopy under 1000× magniﬁcation. The optical microscopic observations showed the formation of spherical vesicles [20]. Another important and more relevant study has been done when protransferosomal gel (PTG) bearing levonorgestrel was observed under a cross polarizer before and after reconstitution (hydration of the incorporated vesicles) [50]. The PTG showed birefringent streak lamellar structures in liquid crystalline form (Fig. 10a). Hydration of this gel formed spherical vesicular structure (Fig. 10b). The obtained results were attributed to the difference in the water content between both cases. The limited water amount made the PTG form a mixture of lamellar liquid crystals and vesiculating lamellas linked together. Swelling of the lipid bilayer occurred by the addition of water due to interaction of water with polar groups of surfactants. Above a limiting concentration of solvent, the bilayers formed vesicular structures [119]. Regarding VPGs, generally only a few techniques are suitable to get a better insight into the supermolecular structures and alterations of these semisolid preparations namely, differential scanning calorimetry (DSC) and freeze-fracture electron microscopy (FFEM). Their morphology was revealed by (FFTEM) as described by Brandl et al. [57]. Unlike liposomal hydrogels, the inner structure of VPGs was described as a matrix of more densely packed vesicles within the semisolid pastes [63] as shown in Fig. 11. Many factors were found to affect VPG morphology and their effect was studied by Brandl including, the inﬂuence of the mechanical stress, lipid content, and lipid type. Processing using magnetic stirring resulted

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Fig. 12. Freeze-fracture electron micrograph of vesicular phospholipid gel based on a) 450 mg/g lipids, b) 500 mg/g lipids, and soy PC, prepared by high pressure homogenization (10 cycles at 70 MPa).

Fig. 13. Tapping mode atomic force microscopy (AFM) imaging (amplitude data) of (a) gel core liposomes, (b) after addition of 15 mM Triton X-100, bar = 500 nm.

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For any topical gel formulation, the rheological properties play an important role in determining the efﬁcacy of the gel in delivering the molecules onto or across the skin. Rheological properties greatly affect spreadibility, adhesiveness, drug release from semisolid formulations, and subsequent penetration into the skin [124–126].

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have to be done in order to fully investigate the inﬂuence of the organogel components and their concentration on the type of bonds forming microstructures and the way they entangle together to form a threedimensional gel network [113].

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the optical transparency of LOs make their study viable by various spectroscopic techniques, including, nuclear magnetic resonance (NMR) spectroscopy (i.e., 2H NMR, 31P NMR), and Fourier transformed infrared (FTIR) spectroscopy [86,87]. SEM and TEM [86], dynamic and static light scattering (elastic or quasielastic light scattering techniques QLS) [122], small-angle neutron scattering (SANS), small-angle X-ray scattering (SAXS), and atomic force microscopy (AFM) were used to decipher the molecular packing within the organogel network [87,123]. These techniques help the elucidation of many features of organogels at 1 to 1000 nm scale. Moreover, the use of AFM helps in the direct visualization of these microstructures throughout the gel mass in its native state and provides structural details on the larger length scales. However, many more studies still

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Fig. 14. Photomicrographs of gel core liposomal formulation following treatment with Triton X-100 (A) after gelling in the core and (B) before gelling in the core.

Fig. 15. Different morphological phases of micelles. (a) Lamellar; (b) inverted micelles within a bilayer; (c) tubular inverted micelles within bilayers; (d) close-packed arrays of inverted micelles within bilayers; (e) hexagonal-II; (f) cubic phase.

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Fig. 17. Comparison of the effects of cellulose acetate membrane with guinea pig skin on release rate of ketorolac tromethamine from an organogel formulation.

they found that an increase in the viscosity and in gel strength was observed by increasing lecithin concentration. In another study, the viscosity of a lecithin microemulsion organogel formulation was investigated. They were found to range from 350 to 650 poise. It was also observed that an increase in the water content or lecithin/IPM ratio resulted in an increase in the organogel viscosity [130].

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Dialyzing methods using artiﬁcial membranes were used in order to investigate drug release in vitro [115]. In order to evaluate the inﬂuence of various artiﬁcial membranes on the release rate, studies were performed on lecithin microemulsion gel containing ketorolac tromethamine using both cellulose acetate and silicone elastomer. A signiﬁcant decrease (p b 0.05) in ketorolac tromethamine release was obtained when using silicone as a synthetic membrane. The release rate with cellulose acetate membrane was 3 times higher (22.746 μg/cm2/h) than that observed with silicone membrane (7.678 μg/cm2/h). This may be due to the differences in molecular weight cut-offs between cellulose acetate (3500 Da) and silicone elastomer membrane. Moreover, this artiﬁcial cellulosic membrane showed extremely higher release rates when compared with guinea pig skin (Fig. 17) [115]. Skin permeation studies can be conducted by both in vivo and in vitro methods [131]. Literature survey demonstrated that in vitro methods are more commonly used than in vivo ones. This may be attributed to the preference of not using live animals. Moreover, using human skin, closer estimates to human exposure may be obtained. The primary limitation described for in vitro percutaneous penetration testing is that sink conditions of the peripheral blood ﬂow may not be fully reproduced. Generally, incorporation of the drug in such phospholipid based system enhances drug permeation compared to conventional dosage form or compared to the drug solution [12,45,54,110]. However, the most important ﬁnding in both release and permeation tests is to determine the different inﬂuencing factors, which are the same in both cases. These factors include the type and amount of drug incorporated [22,76,115], phospholipid type and concentration [76,130] and other excipients' type and amount such as solvents and cosurfactants [130]. Size and surface charge of liposomes contribute also to the factors inﬂuencing drug permeation and deposition [132]. It was reported that, large multilamellar vesicles have more ﬂexible membranes facilitating the permeation of the bilayer into the pores of the stratum corneum [131].

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The viscosity of liposomal dispersions was expected to be initially low which justiﬁed the embodiment of such dispersions into a gel matrix. In a recent study, the viscosity of a transferosomal suspension was low (28.25 ± 0.44 mPaS) which was not suitable for transdermal use. The viscosity was signiﬁcantly increased (p b 0.05, t-test) in the case of the transferosomal gel (12,503.33 ± 0.14 mPaS) due to the incorporation of the formulation into 1% carbopol 940 gel matrix, which made the formulation more suitable for transdermal administration [37]. A study was conducted on a topical temoporﬁn (potent second generation photosensetizer used in topical photodynamic therapy)-loaded liposomal hydrogel in order to determine the relationship between rheological properties of gels and the skin penetration of temoporﬁn [67]. Moreover, the inﬂuence of carbomer (the gelling agent) concentration, and phosphatidylcholine (PC) content of lecithin, on viscoelastic properties and viscosity of the prepared liposomal gels was examined. A plastic ﬂow behavior was observed from the prepared liposomal hydrogels. The increase of carbomer concentration resulted in a domination of elastic over viscous behavior of gels. An inverse relationship between the elasticity of gels and drug penetration was revealed. Thus, increment of carbomer concentration reduced the temoporﬁn penetration. Liposomal gels containing lecithin of low PC-content (i.e. smaller purity) exhibited a more elastic solid behavior than gels containing lecithin with high PC-content, and thus smaller temoporﬁn penetration [67]. In this regard, it should be noted that lower purity grades of lecithin also failed to form gel properties in lecithin microemulsion organogels [113]. Unlike liposomal gels, VPGs and LMBGs intrinsically have a semisolid consistency without the addition of a gelling agent. The viscosity and gel strength of VPGs were found to increase by increasing the lipid concentration. In a recent study, the viscosity of VPG formulations was determined to range from 4.8 to 24.7 Pa.s when using lipids in concentrations ranging from 300 to 550 mg/g [15]. Lecithin microemulsion organogels have been extensively studied for their rheological behavior and have been determined to be viscoelastic in nature which is a desired property [88,90,127]. In apolar solvents (i.e., prior to gelling) these systems exhibit Newtonian behavior while upon addition of the polar phase, they follow Maxwell's rheological (viscoelastic) behavior. Selection of the type of organic solvent, the type and amount of polar solvent, and the concentration of lecithin was found to signiﬁcantly inﬂuence the structural stability and rheological behavior of LOs. Thus by modiﬁcation of these parameters one can obtain LOs with the desired viscoelastic property. For example, Scartazzini and Luisi used different types of organic solvents, for LO preparation, including linear and cyclic alkanes and amines and measured the viscosity of the various formed organogels. They found that when linear alkanes were used organogel viscosity was increased due to the obtained highly organized LO structure [87,128]. Schurten-berger et al. [129] studied the effect of the gelator concentration on the viscosity of the organogel and

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Fig. 16. Micro-structure of organogel with long tubular network.

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[1] B.C. Finnin, T.M. Morgan, Transdermal penetration enhancers: applications, limitations, and potential, J. Pharm. Sci. 88 (1999) 955–958. [2] N. Chandrashekar, R.S. Rani, Physicochemical and pharmacokinetic parameters in drug selection and loading for transdermal drug delivery, Indian J. Pharm. Sci. 70 (2008) 94. [3] M.B.R. Pierre, I.d.S.M. Costa, Liposomal systems as drug delivery vehicles for dermal and transdermal applications, Arch. Dermatol. Res. 303 (2011) 607–621. [4] S. Abrol, A. Trehan, O. Katare, Formulation, characterization, and in vitro evaluation of silymarin-loaded lipid microspheres, Drug Deliv. 11 (2004) 185–191. [5] Y.S. Elnaggar, M.A. El-Massik, O.Y. Abdallah, Fabrication, appraisal, and transdermal permeation of sildenaﬁl citrate-loaded nanostructured lipid carriers versus solid lipid nanoparticles, Int. J. Nanomedicine 6 (2011) 3195–3205. [6] Y.S. Elnaggar, M.A. El-Massik, O.Y. 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The scope of this review was to investigate the gelling of phospholipid-based nanostructured systems, namely liposomes and microemulsion lecithin gels. Throughout the review lecithin nanocarrier-based gels were compared to conventional gels and corresponding liquid status nanocarriers. Aspects reviewed encompassed state of art, applications and characterization. Liposomal gels and lecithin microemulsion gels were reported to be more acceptable topically than the liposomal dispersion and microemulsions. Moreover, both systems exhibited numerous advantages compared to conventional formulations, including enhanced transdermal penetration, higher protection of the entrapped drug, increased solubilization and duration of action. When lecithin is incorporated in the oily phase of microemulsions it greatly reduces the concentration of the surfactants used due to its good emulsiﬁcation properties. Thus, lecithin microemulsion gels are nonirritating unlike other microemulsion formulations. An advantage for microemulsion gels over liposomal one was elucidated regarding thermodynamic stability and technical feasibility [115]. Nevertheless, detailed comparison between liposomal gels and lecithin microemulsion gels is still required. Such comparative study would demonstrate the most suitable use of each system and facilitate rational selection of the appropriate formulation. Another uncovered research point is the potential of VPGs and M-i-L as novel

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delivery systems for dermal drug delivery. Aforementioned research 924 perspectives about lecithin-based nanostructured gels are currently in- 925 vestigated by our work group. 926

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The effect of drug type on the release rate was investigated in a study of the release of two model compounds, one hydrophilic (calcein) and one lipophilic (griseofulvin), from liposomal gels. It was found that for hydrophilic drugs that cannot diffuse across lipid membranes, drug release is mainly dependent on liposome membrane rigidity and mechanical stability during their dispersion in the semisolid formulation. When using amphiphilic or lipophilic drugs, the main factor controlling drug release is the physicochemical properties of the drug such as lipophilicity and solubility [22]. Nasseri et al. [115] investigated the inﬂuence of some formulation variables on ketorolac tromethamine release from lecithin microemulsion gel. The data revealed that the release rate was directly proportional to drug concentration due to the increase in thermodynamic activity until reaching a limiting value equal to the saturated solubility. On the other hand, ketorolac tromethamine release was inversely proportional to lecithin concentration due to the decrease in thermodynamic activity of the drug caused by increased lecithin concentration. At higher lecithin concentrations, there is a condensed network structure of long cylindrical micelles with a very high viscosity. Ketorolac tromethamine entrapment within this network reduces the amount of free drug available for release, decreasing the drug release rate across the membrane [90]. The effect of water concentration on the release rate of ketorolac tromethamine was also investigated. Results demonstrated that by increasing organogel water content drug release was decreased. With increasing amounts of water, spherical reverse micelles convert into cylindrical micelles and then into long and ﬂexible micelles that entangle and form three-dimensional networks with a high viscosity entrapping drug molecules [115]. The potential of VPGs as depot formulations for sustained release of injectable drugs was assessed [15,75]. Tian et al. [15] have investigated the release of erythropoietin from VPGs. Results inferred that VPGs delivered the protein over prolonged periods of time at close to linear kinetics without any burst effect. In addition the inﬂuence of both the lipid content and charge on the release behavior had been studied. It was found that increasing the lipid concentration results in a decrease in the release rate. Similar results were obtained in the study done by Tardi [133] who studied the in vitro release behavior of VPGs using Calcein (Mw 623) as a hydrophilic model. Despite the aforementioned advantages, utilization of VPGs for skin drug delivery has not so far been investigated.

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Lecithin-based nanostructured gels for skin delivery: an update on state of art and recent applications. - PDF Download Free (2025)