Lecithin Organogels as a Potential Phospholipid-Structured System for Topical Drug Delivery
1. INTRODUCTION
The topical administration of drugs, in order to achieve optimal cutaneous and percutaneous drug delivery, has recently gained an importance because of various advantages such as ease of administration and delivery benefits etc. In search of a vehicle to deliver the medicament into the skin layers (cutaneous delivery), or through the skin and into the systemic circulation (percutaneous absorption), varied kinds of formulation systems and strategies have been evolved1-6.
Amongst the many, the lipid-based formulations have been in use since decades7-11 However, of late, there has been a surge in their number with a wide variation and flexibility in the interior designs and structures. The importance of lipids has especially increased after realizing the utility of phospholipids, the natural bio-friendly molecules, which in collaboration with water can form diverse types of supramolecular structures12-14 .the latter, can also be modified sometimes by using some polymeric substances and solvents etc., to serve the predestined delivery of the molecules.
The topical delivery has been attempted and made successful using a number of lipid-based systems viz. vesicular systems15, lipid microspheres16, lipid nanoparticles17, lipidmicroemulsions18 and polymeric gels19.
In a recent development, phospholipids in conjunction with some other additives have been shown to provide a very promising topical drug delivery vehicle, i.e., lecithin organogel (LO). LOs are thermodynamically stable, clear, viscoelastic, biocompatible, and isotropic gels composed of phospholipids (lecithin), appropriate organic solvent and a polar solvent20, 21 .LOs, the jelly-like phases, consist of a three-dimensional network of entangled reverse cylindrical (polymer like) micelles, which immobilizes the continuous or macroscopic external organic phase, thus turning a liquid into a gel22 .
The formation of a three-dimensional network in the organogel is the result of transition at the micellar level in a low viscous newtonian liquid consisting of lecithin reverse micelles in nonpolar organic liquid.23, 24 This spherical reverse micellar state of lipid aggregates, turns on to form elongated tubular micelles with the addition of water, and subsequently entangle to form a temporal three-dimensional network in the solution bulk22, 24-26.The latter serves to immobilize the external organic phase, thus producing a gel form or the jelly-like state of the initial nonviscous solution. However, the transparency and optical isotropy of the organogel remains as before. The supramolecularly associated micellar aggregates in the entangled state bear resemblance with that of uncrossed polymers in semi-dilute or concentrated solutions27,28.For this reason these systems are often called polymer like micelles and are also termed as living or equilibrium polymers, wormlike or threadlike micelles29-31
1.1 Advantages
Ease of preparation and scale-up, easier quality monitoring, thermodynamic stability, enhanced topical performance along with biocompatibility and safety upon applications for prolonged period, makes the organogels a vehicle of choice for topical drug delivery. Their skin penetration enhancing ability has also been well recognized. Table 1 illustrates some of the pharmaceutically advantageous properties of LOs.
Table 1: Various Meritorious Features of Lecithin Organogels
S. No.
Salient Features
Reference
1
Template vehicle
LOs provide opportunities for incorporation of wide range of substances with diverse physicochemical characters viz. chemical nature, solubility, molecular weight and size etc.
20, 21,32
2
Process benefits
Spontaneity of organogel formation, by virtue of self-assembled supramolecular arrangement of surfactant molecules, makes the process very simple and easy to handle.
26
3
Structural/physical stability
Being thermodynamically stable, the structural integrity of LOs is maintained for longer time periods.
22-24, 26
4
Chemical stability
LOs are moisture insensitive and being organic in character also resists microbial contamination.
20, 21, 26
S. No.
Salient Features
Reference
5
Topical delivery potential
Being well balanced in hydrophilic and lipophilic character, they can efficiently partition with the skin and therefore enhance the skin penetration and transport of the molecules.
LOs also provide the desired hydration of skin in a lipid-enriched environment so as to maintain the bioactive state of skin.
32-34
6
Safety
Use the biocompatible, biodegradable and non-immunogenic materials makes them safe for long-term applications.
35-37
2. Lecithin Organogels: An Overview
The first description of LOs was given in an article published by Scartazzini and Luisi in the year 1988.20 the authors were investigating the suitable conditions for soy lecithin to form reverse micelles. In these experiments, water was added to various organic solutions of purified soybean lecithin. It was observed that addition of trace amounts of water into nonaqueous solutions of soy lecithin caused an abrupt rise in the viscosity (104-106 times), producing a transition of the initial non-viscous solution into a gel or jelly-like state. The amount of water required to produce the gel was found to be critical. The phenomenon was observed with various non-polar media and the list includes more than fifty solvents.20, 21 this fact allows one to consider the organogel formation by the water addition as a common phenomenon, being inherent in the nonaqueous solutions of lecithin. Subsequent to this observation, further experiments by Scartazzini and Luisi,20 and Schurtenberger et al.21 involved preliminary investigations on the formation as well as the structural aspects of LOs. Soy or egg lecithin in the concentration range of 50 to 200 mM in different organic solvents such as linear or cyclic alkanes, esters of fatty acids, and amines etc., was noted to be effective for gel formation. By now, LOs have been studied extensively in many laboratories worldwide, with regard to their varied aspects such as formulation components, formation and gelling mechanism, physicochemical properties etc., and have also been proposed as a matrix for topical drug delivery.
2.1 Organogel Composition
The organogel matrix chiefly consists of a surfactant (lecithin) as gelator molecules, a non-polar 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.23, 26 the latter are mainly separated from soy bean and egg yolk. Lecithin is a trivial name for 1, 2-diacyl-sn-3-phosphocholine. It belongs to a biologically essential class of substances termed phosphoglycerides or phospholipids. The latter form the lipid matrix of biological membranes and also play a key role in the cellular metabolism.38 As a biocompatible surfactant, it is widely used in everyday life including human and animal food, medicine, cosmetics and manifold industrial applications.39, 40 Synthetic lecithins containing residues of saturated fatty acids failed to form organogel.22, 26, 41 The gelling formation was also not observed with hydrogenated soybean lecithin.26 These studies indicate the importance of lecithin in the naturally occurring form which contains unsaturated fatty acids.
With reference to the effect of instauration in phospholipids on organogelling, no such systematic investigative studies have been conducted till date. However, it has been established that instauration in phospholipid molecules is a desired property for the formation of lecithin organogels. This may be attributed to its impact on the nature of self-assembly in which the phospholipid molecules associate and form the microstructures. The instauration contributes to the volume factor of the non-polar region of phospholipid molecules and may alter the value of critical packing parameter (CPP), favoring the formation of reverse micellar structures. And probably the size of such structures is also one of the crucial factors that play an important role in the gelling process. In addition to the effect on CPP and size of the microstructures, the property of instauration can also be interpreted in terms of degree of hydration of phospholipid molecules that it provides.
In contrast to the saturated hydrogenated phospholipids, instauration in phospholipid molecules would result in better hydration of the polar head group, thereby increasing the area per lipid polar head group. Consequently, larger area and relatively smaller volume would favorably alter the spontaneous curvature of lipid monomers for the formation of micelles and subsequently their self-assembly to form micellar network. Additionally, the purity of lecithin also plays a critical role in the organogel formation. Poorly purified lecithin does not possess gel-forming properties and it has been demonstrated that lecithin should contain at least 95% phosphatidylcholine content for the preparation of organogels.20, 21, 26
Besides lecithin as gelator molecules, the role of organic solvent in providing the desired solvent action onto the gelator molecules is much emphasized.20, 26 A large varieties of organic solvents are able to form gel in the presence of lecithin. Among them are linear, branched and cyclic alkanes, ethers and esters, fatty acids, and amines. Specific examples include ethyl laureate, ethyl myristate, isopropyl myristate (IPM), isopropyl palmitate (IPP), cyclopentane, cyclooctane, trans-decalin, trans-pinane, n-pentane, n-hexane, n-hexadecane and tripropylamine etc.21 amongst the above, the fatty acid esters, i.e., IPM and IPP are of particular interest for topical applications of LOs. This has been attributed to their skin penetration enhancing property besides their biocompatible and biodegradable nature.42-45
The third component, a polar agent, acts as a structure forming and stabilizing agent and has a very crucial role to play in the process of gelling. The gel-forming ability of the polar solvent is governed by its physicochemical properties.30, 46, 47 It has been established that gel forming solvents possess high surface tension, relative permittivity (dielectric constant), solvent polarity (polarity index), and a strong tendency towards hydrogen bonding. 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 or organogel.30
As described earlier, the major limitation in the formation of LOs is the requirement of high purity lecithin. The high purity grade lecithin is not only expensive but also difficult to obtain in large quantities. However, recent reports indicate the incorporation of synthetic polymer i.e., pluronics in LOs, for their usefulness as co-surfactants and stablizers.48-51 It has been shown that the inclusion of pluronics as co-surfactant makes the organogelling feasible with lecithin of relatively lesser purity.51
The term “pluronic” refers to a series of non-ionic closely related block copolymers of ethylene oxide and propylene oxide.52 Also known as “Poloxamers”, “Poloxamer polyols” or Lutrols®, these are primarily used in pharmaceutical formulations as co-surfactants, emulsifiers, solubilizers, suspending agents and stablizers. These pluronic containing LOs have been termed as “pluronic lecithin organogels”, “poloxamer organogels”, “pluronic organogels”, “PLO gel” or simply “PLOs”.
2.2 Phase-Behavior of Organogels
The phase-behavior of a ternary system of lecithin/organic solvent/ polar solvent is mainly governed by the concentration of polar solvent and lecithin.26, 53, 54 The same is defined in terms of the parameter, nw, i.e., molar ratio of polar solvent to lecithin (nw = [polar solvent]/ [lecithin]).20, 21 It is noted that the organogel as a homogenous phase exists over a very narrow range of polar solvent concentration.24, 46
Lately, the phase behavior of lecithin in n-decane employing water as the polar solvent has been discussed.26 initially, with the addition of water, the thickening effect is observed at a certain specific molar ratio of water to lecithin. After this threshold concentration, further addition of water leads to a sharp increase in the viscosity and the formation of organogel.
The organogel state is maintained up to a particular molar ratio of water to lecithin, designated as ncr. At the state where nw is equal to ncr, the maximum viscosity of organogel is achieved. On continuing the water addition above the ncr, i.e., at nw > ncr, the three-dimensional network collapses and separation of the homogenous organogel takes place into a two-phase system consisting of low viscous liquid and a compact organogel or jelly-like phase. At still higher concentrations of the polar phase, the transformation of the separated compact organogel into a solid, non-transparent precipitate is observed.
The parameter ncr is considered as a useful, quantitative and reproducible parameter to characterize various organogels. It is the critical molar ratio of polar solvent to lecithin molecules at which maximum amount of external organic phase is entrapped, and thereafter the phase separation of the organogel accrue.26, 55, 56 The ncr values can be easily determined with the help of rheological measurements or visual and optical observations of a ternary system between cross polarizers.
In most of the solvents employed in the preliminary studies on lecithin organogels, the ncr values were found to be in the range of 1 to 12 (as shown in Table 2) employing 80:16:04 weight percents of lecithin, organic solvent and water.20, 21
Table 2: ncr Values with Different Organic Solvents Employed in Lecithin Organogel Systems Composed of Soyabean Lecithin/Organic Solvent/Water in 80:16:4 Weight Ratio 20, 21
Solvent ncr
1,7-octadiene 7
Butyl laurate 7
Cyclododecane 12
Cyclooctane 7
Dibutyl ether 6
Ethyl myristate 5
Isooctane 2
Isopropyl myristate 3
Isopropyl palmitate 3
n-hexadecane 1
n-hexane 3
n-octane 2
Trans-decalin 5
Tributylamine 2
Triisobutylamine 3
Further, the phase behavior of the ternary system is also shown to be dependent on lecithin concentrations employed for the formation of organogel system, and the phase separation has been noted to be abolished when the concentration of lecithin exceeds 200 mg/ml.26, 53, 54 In one study, 26 using n-decane as the external media and lecithin at concentration smaller than 200 mg/ml, the gel formation was observed at nw = 1, while water was used as a polar additive. With subsequent addition of water (i.e., at nw = ncr), the organogel with maximum viscosity was obtained, but the phase separation of organogel occurred at nw > ncr, i.e., at nw = 3.2-3.4, and a separated semisolid phase was found. However, using lecithin concentration of more than 210 – 220 mg ml-1, the phase separation ceased. In this case the transparent and isotropic gel state was maintained even at nw ? 3.2-3.4.
2.3 Organogel Structure and Mechanism of Organogelling
The organogelling or the gelation of the lecithin solutions in organic solvents is induced as a result of the incorporation of a polar solvent. Lecithin, when being dissolved in non-polar media alone, self assembles into reverse spherical micelles at a concentration of about 0.01mM.57 the enormous uniaxial growth of these spherical reverse micelles and subsequent transformation into tubular or cylindrical micellar aggregates (sphere-to-cylinder transformation) is triggered by the addition of small and critical amounts of polar additive as shown in Figure 2. The molecules of polar solvent, on addition, bind in stochiometric ratios to the hydrophilic head portion of the lecithin molecules in such a way that two adjacent lecithin molecules are bridged together by one polar molecule.23, 30 This leads to the formation of linear networks, from hydrogen bonds formed by the polar molecules and phosphate groups of lecithin molecules, and in turn to the onedimensional uniaxial growth of lecithin reverse micelles. Further increase in the amount of polar additive results in the formation of flexible, long tubular micelles of 2.0 to 2.5 nm radius and hundreds to thousands of nanometers in length.53, 54 After reaching a critical length, these extended micelles begin to overlap, entangle themselves and build up a transient threedimensional network.24, 26, 58-62 This marks a crossover to a system characterized by increased viscosity and viscoelastic properties. Instead of a low viscous solution, a jelly-like phase, i.e., LO is obtained. The LO thus obtained contains a considerable amount (approximately 85 weight percent) of external phase, i.e., the organic liquid, entrapped in the spaces between the entangled reverse micelles. The hydrogen bonding network built up by molecules of polar additive and phosphate groups is also accompanied by stiffness of the phospholipid molecule in the region of phosphate group and glycerol residue, which stabilizes the micellar aggregates. In case of PLOs, the mechanism of gelling and the structural network may be related to the synergistic contribution of both phospholipids as well as polymeric co-surfactant molecules, in their respective hydrated states. However, till date no scientific reports have appeared related to the structural details of PLOs gels.
The contribution of organic solvent as an external phase in the gelling process is also indicated, as it influences the micellization of lecithin monomers. The requirement of the specific organic solvents for the purpose indicates that it provides appropriate environment for the intermolecular and intra-molecular interactions in gelator molecules and the organic solvent molecules. In terms of the molecular-shape approach developed by Israelachvili et al63 the aggregate transformations (i.e., sphere-to-cylinder transformations) are determined by a change of a curvature for the amphiphile monolayer. In particular, the effects of polar solvent introduced into spherical lecithin micelles may be associated with an increase in the cross-sectional area of the lecithin polar region in which the solvent is arranged. The shape of the hydrated molecules is close to a cylinder.64 this leads to packing constraints in the spherical micelles that are diminished through the transition into the cylindrical ones with a smaller curvature.
2.4 Characterization of Organogels
In contrast to the ease of preparation, characterization of LOs is relatively complicated on account of their interior structural design build up on the self-associated supramolecules. These microstructures, the resultant of varied polar non-polar interactions, are highly sensitive and pose difficulties in the investigative studies. However, different characterization studies are extremely useful while investigating the potential applications of organogel systems as a topical vehicle.
For instance, it has been reported that many of the physicochemical properties of LOs viz. rheological behavior, physical and mechanical stability, and drug release behavior are dependent upon how do molecules arrange themselves to provide the specific structural network within the organogel system.20-22
2.4.1 Structural Features
An efficient characterization methodology for any organogel system begins with its structural elucidation. Molecular architecture of LOs has been evaluated using a wide range of different techniques over the years, but a complimentarity of methods is generally required to fully characterize these systems. The isotropic nature and the optical clarity of LOs, makes their study feasible by various spectroscopic techniques viz. 2H NMR, 31P NMR, and Fourier Transformed Infrared (FTIR) spectroscopy. Luisi et al.20, 21 employed 2H NMR and 31P NMR spectroscopy for studying the phase behavior of soybean LOs, to establish the absence of birefringence and liquid crystalline phases.
Various techniques have been employed to find the nature of binding forces responsible for association of monomers to form self-assembled structures and FTIR spectroscopy has been found to be successful in establishing the hydrogen bonding as one of the major driving forces for the self-assembly of organogelator molecules in the organic solvents.24, 25, 28, 30, 65 The knowledge of molecular packing within the organogel network has been obtained using scanning and transmission electron microscopies (SEM and TEM),20 dynamic and static light scattering (elastic or quasielastic light scattering techniques QLS),21, 22, 66-68 small-angle neutron scattering (SANS), small-angle X-ray scattering (SAXS) and atomic force microscopy (AFM).21, 22, 69-72
These techniques allow many features of organogels to be deciphered at 1-1000nm scale. Recently, SAXS and AFM have become important tools in determining the molecular arrangement of long range structures such as LOs, along with the absolute quantities such as diameter, lengths or topologies in gels.72, 73 The scattering information (SAXS and SANS measurements) on organogels, which could be obtained even in undiluted samples (i.e., without disturbing the originality of the system), combined with mathematical analysis provides information on static correlation length “?”, the mesh size of the network (or the number density of entanglements ‘?’), diffusion coefficients and flexibility of the fibrous network etc., along with the structural features of the cross-sections of LOs.20, 21, 70, 71, 74, 75 The direct visualization of the gel in its naïve state is possible using AFM, which allows observing the microstructures of the fibrous network throughout the gel mass. It also provides structural details on the larger length scales, i.e., where micellar fibers or chains aggregate into large sized bundles. Thus, multiple instrumental techniques based on microscopy along with spectroscopic and scattering analysis can help reveal the structural details of the lecithin organogel systems.
2.4.2 Rheological Behavior
For any vehicle to be used for topical drug delivery applications, it is essential to study its rheological behavior. The latter is important for its efficacy in delivering the molecules onto or across the skin site. The critical parameters like spreadibility, adhesiveness (property related to bioadhesion on skin site), cohesiveness (which indicates structural reformation following application of shear stress, and gel consistency need to be modified in a favorable manner.
LOs have been studied extensively for their rhelogical attributes and determined to be viscoelastic in nature.26, 29, 30, 62 These systems, prior to gelling, i.e., before the addition of polar phase, exhibit Newtonian behavior but follow Maxwell’s rheological (viscoelastic) behavior on addition of the polar phase.30 It has been reported that the Maxwell rheology model holds good for systems with supramolecular organization, consisting of temporal three-dimensional network of entangled micelles.26, 30, 47, 61 Also, the desired viscoelastic property can be managed by modifying the various formulation components viz. selecting the type of organic solvent, concentration of gelator or cosurfactant, or the type or amount of polar agent, which significantly influence the structural stability and rheological behavior of organogels. For example, Scartazzini and Luisi carried out the dynamic shear viscosity (denoted as [ETA*]) determinations of various soy lecithin organogel systems, prepared using different types of organic solvents viz. linear and cyclic alkanes,and amines etc. The higher values of [ETA*] obtained using linear alkanes were related to the higher state of structural organization in LOs.21, 22 Similarly, Schurtenberger et al.76 found that increasing the gelator concentration leads to an increase in the viscosity and in turn the gel strength of a soy lecithin/IPP organogel matrix.
2.4.3 Phase Transition Temperatures
The phase behavior of organogels is subjected to vary on changing temperature conditions.21 The phase transition temperature (PTT), i.e., sol-to-gel “TSG” or gel-to-sol “TGS”, gives an insight into the nature of microstructures that form the gelling cross-linked network. The phase transition temperatures also help in optimizing the organogel composition. In one such study, concentration of gelator in a given LO formulation was optimized by monitoring the PTTs of the organogel.77 It also reveals the micro structural homogeneity of the prepared organogel system. For example, a narrow PTT range (i.e., 3-5 ºC) is indicative of homogenous microstructures within the gel.77, 78 For the determination of PTTs, hot stage microscopy (HSM) and high sensitivity differential scanning calorimetry (HSDSC) have been reported to be useful as accurate and sensitive techniques.21, 23, 77 However, the “inverse flow method”, a simple technique based on visual observations has also been employed.79
2.4.4 Water Content
Water content of a organogel system is critical, as the water loss by evaporation can lead to consequent decrease in viscosity thus affecting the gel stability. Gambri et al.80 have proposed near-infrared (NIR) spectroscopy as simple, rapid and non-destructive technique for determining the water content in LOs. The researchers carried out NIR studies on lecithin/IPP/water organogel system by measuring the water absorption in the NIR region (1800-2200 nm). In this region, water shows a strong absorption peak at 1918 nm due to H-O-H stretching overtones, which are easily detectable and quantifiable. A calibration curve was generated using 1ml samples of lecithin gel containing different amounts of water (nw ranging between 0.5 and 3), using as blank a lecithin solution (at same concentration) in IPP without any water addition. Various prepared organogel samples were then analyzed for water content after different lengths of time. Satisfactory results in terms of reproducibility and system precision were obtained. In addition, this technique has also been proposed to be useful to identify phase separation (syneresis) in the prepared organogel formulations.
3. TOPICAL DRUG DELIVERY APPLICATIONS OF LECITHIN ORGANOGEL-BASED SYSTEMS
LOs have generated considerable interest over the years as a potential topical drug delivery vehicle.81 the co-existence of organic and aqueous phase by means of structurally well-defined micellar network of phospholipids, large interfacial area, and possibility to entrap solutes within the gel matrix along with long-term stability makes them useful for variety of applications. The topical applications of various drug containing LO systems has been demonstrated to significantly enhance the skin permeation and absorption of both lipophilic and hydrophilic substances. The organized micro structural matrix, amphiphilicity, super-solubilizing capacity and interaction of the bio-lipids with skin tissues are some of the major promoting factors for an enhanced transport of drug molecules into or across the skin. Therapeutic compounds of different chemical and physicochemical background such as muscle relaxants, steroids, hormones, analgesics, antiemetics, cardiovascular agents, antithyroid drugs, and some macromolecules have been incorporated in the LOs with some very encouraging results.
3.1 Dermal Drug Delivery
Enhanced skin penetration and site-specific delivery of bioactive into the deeper layers of skin has been achieved employing organogels as a topical vehicle. Topical administration of a LO formulation containing therapeutically effective amount of digoxin has been found to be effective for the treatment of muscle spasm as well as in the management of peripheral or neuropathic pain.82 Friedman has reported the subcutaneous delivery of cyclobenzaprin, a muscle relaxant, using LO as a topical vehicle.83 The muscle relaxant administered in lecithin-IPM organogel is shown to provide immediate relief of pain resulting from bruxism (tooth grinding) and tooth clenching.
Remarkably high skin penetration of phytosphingosine or sphingosine, a “Protein Kinase C” (PKC) inhibitor, incorporated in LO gel, has been reported.84 The prepared organogel-based formulation was found to effectively inhibit the PKC activity in the skin and mucocutaneous junction, thus useful in the topical treatment of keloids and hypertrophic or burn scars. It was also shown to be effective in psoriasis, psoriatic arthritis or any other inflammatory condition of the skin which involves PKC. In a similar study, topical application of phytosphingosine (0.1 to 7.5 % w/w), formulated as PLO employing lecithin, IPP, ethanol, water and pluronic F-127, is noted to be effective for the treatment of tendons affected by tenosynovitis in carpal tunnel syndrome.85
A recent U.S. patent granted to Crandall and Wilson (2001), describes the PLO formulation for the effective delivery of antipsoriatic agents and for drugs used in eczema.51 The patented formulation is composed of lecithin (containing ? 95% phosphatidylcholine) dissolved in IPP or IPM to achieve a final concentration range of 20-40% v/v, a suitable amount of pluronic, and water with or without short chain alcohol. The composition is also proven to be effective for moisturizing and rejuvenating the keratinous tissue including skin, hair and fingernails. Padilla et al.86 have also described the efficacy of PLOs for topical use of local anesthetics and NSAIDs.
It is inferred that for those orofacial disorders that are regional, near the surface and chronic, the LOs are more advantageous over systemic administration of drugs because of the rapid onset of action with low side-effect profile. In one such study, significant improvement in the analgesic action of ketamine hydrochloride and amitryptiline hydrochloride formulated in LO has been reported.87
The use of these compounds for topical pain relief is otherwise limited due to their poor skin penetration and partitioning properties. Similarly, a PLO gel containing 3 to 30% extract of Arnica Montana in combination with topical analgesic or systemic opioid is proven to be useful in reducing inflammation and providing relief from both peripheral and central pain.88 Flores et al.89 have prepared a ketamine PLO gel with an aim to improve the analgesic effect of ketamine. The use of ketamine is otherwise restricted due to the associated systemic side effects along with extensive first pass metabolism.
Developed PLO gel of ketamine, when applied directly to the site of application alleviates the sympathetic or neuropathic pain and also avoids the side effects associated with the drug. Selective delivery of an anti-androgen compound into the pilosebaceous units has also been reported.90 An organogel-based (LO or PLO) formulation containing extract of saw palmetto (having antiandrogen agent as a principal constituent) along with acyl carnitine and coenzyme Q has been reported as an effective formulation for the topical treatment of androgenic alopecia. LOs have also been found to be an excellent matrix for the delivery of a macromolecule with a molecular weight of 33000 daltons.91 PLO gel containing anti-inflammatory macromolecule bromelain (15%) along with capsaicin (0.025%) has been found to be an effective anti-inflammatory composition. Direct application of this PLO gel at the site of inflammation has been found to be useful for treating a variety of inflammatory indications.
3.2 Transdermal Drug Delivery
Organogel systems have also been used as a matrix for transdermal transport of different therapeutic compounds. Willimann and Luisi32 were the first to study LOs as matrix systems for transdermal transport of drugs. The authors investigated the transdermal delivery of scopolamine (an active drug against motion sickness) and broxaterol (a bronchodilatory agent) employing lecithin gel composed of 200 mM of lecithin in a biocompatible solvent IPP, in two separate studies. Scopolamine and broxaterol was solubilsed in the gel up to a concentration of 40 mg/ml and 75 mg/ml, respectively. Significantly higher transdermal flux of scopolamine in lecithin-IPP gel was observed in comparison to that of drug in aqueous solution. Analogous results were obtained with broxaterol incorporated in lecithin organogels.
Later, Willimann and co-workers33 investigated these systems for their role in trans-skin permeation of drugs by employing different organic solvents. LOs were prepared employing soybean lecithin with IPP and cyclooctane. The solubility of various drugs such as nifedipine, clonidine, scopolamine and broxaterol, etc., was noted to be increased in lecithin-IPP solution compared to the drug solubility in IPP alone, suggesting the solubility enhancing properties of the organogels. The IPP-based lecithin gel exhibited higher transdermal transport efficiency than that of cyclooctane lecithin gel. This difference in trans-skin delivery rate could be attributed to the penetration enhancing property of the IPP. The authors, in their study, also suggested the transdermal transport of aminoacids and peptides using LOs. Bhatnagar and Vyas34 have investigated the trans-skin permeability of propranolol hydrochloride, a poorly permeable and water-soluble drug incorporated in LOs, across human cadaver skin. Significantly enhanced (approx. 10 times higher) permeability of micellar-borne drug across the human skin was observed employing drug in 200 mM lecithin/iso-octane/water organogel system in comparison to that of pure drug in solution form or emulsified in the petroleum jelly. Permeation enhancing effect of the lecithin gel was attributed to the vectoring properties of the reverse micelles. It was suggested that the micellar entities being small in size and with hydrocarbon sheath might had been received by the skin barrier as hydrophobic entities, which were allowed for closer interaction with skin barrier leading to enhanced permeation of the drug molecules.
The transdermal delivery and efficacy of various NSAIDs formulated in LOs has also been investigated. In a recent study on indomethacin and diclofenac incorporated in LO gel [IPP (10 ml), soy lecithin (1.9 gm), water (135 ?l)], the transdermal delivery of both the drugs was found to be higher using LO vis-à-vis drug in IPP alone as vehicle.35 In another report, Grace et al.92 have assessed the efficacy and safety of 2% diclofenac in LO in the treatment of pain associated with mild to moderate osteoarthritis, and this novel topical formulation of diclofenac was found to possess a remarkable therapeutic value. Some reports also indicate the use of LOs for the topical administration of systemic hormones. The transdermal delivery of progesterone, incorporated in LOs, has been studied with an aim to minimize the bioavailability fluctuations associated with its peroral administration.93
Similarly, a transdermal formulation of testosterone has also been successfully prepared by incorporating the therapeutically effective amounts of micronized testosterone in a PLO gel.94 Ciribassi et al. have reported the systemic absorption of fluoxetine hydrochloride through skin using PLO as a topical vehicle.95 Fluoxetine hydrochloride incorporated in PLO gel was applied to the hairless portion of the pinnae of cats for its transdermal delivery. Plasma samples were obtained and analyzed for drug content. Results of the study showed that fluoxetine in a 15%w/v PLO gel absorbed through the skin into the systemic circulation. Nicardipine, a calcium channel blocker, because of its low dose, short half life and extensive first pass metabolism, has been incorporated in a LO system in order to achieve systemic absorption through topical route.96 Hoffmann et al.97 have investigated the transdermal delivery of methimazole incorporated in LO, in feline patients.
Authors assessed the serum thyroxine concentrations and clinical response following topical administration of the drug. Significant reduction in serum thyroxine levels was noted in all the cases with almost 100% reduction in the side effects associated with oral methimazole treatment. The transdermal delivery of aromatic tetra-amidines (compounds with antitumour activity) has also been attempted using soy lecithin organogels.80 The in-vivo efficacy was determined in nude mice carrying xenografted tumor cells and was considered to be very encouraging.
In another study on transdermal delivery potential of LOs, Bonina and coworkers 98 have formulated methyl nicotinate-lecithin-IPM organogel and tested in-vivo with human subjects. The results showed rapid induction and intense persistence of methyl nicotinate induced erythema. The solubilization of piroxicam, to increase its transdermal permeation rate, has also been attempted by incorporating the drug in a LO consisting of lecithin/IPM/water.99
A significant inhibition of carrageenan induced rat paw oedema was observed with organogel formulation of piroxicam vis-à-vis marketed transdermal product after 3 h. Thus, with the inflow of several research reports on the varied fundamental aspects of LOs, along with some promising results on the front of drug delivery, these systems can be seen as potential tools in the field of topical drug delivery applications.
Table 3: Topical Delivery of Therapeutic Substances Incorporated in Lecithin Organogels*
Organogel Formulation
Major Findings
Year
Reference
Lecithin (200 mM) IPP gel of broxaterol and scopolamine
Transdermal delivery of compounds
1991
32
Phosphatidylcholine (PC) gel in isopropyl palmitate (IPP) or cyclooctane
Investigated for transdermal transport of various drugs along with amino acids and peptides
1992
33
Propranolol hydrochloride in 200 mM lecithin/iso-octane organogel
Percutaneous delivery of compounds with poor permeability
1994
34
Soybean lecithin/IPP gels containing 10% to 20% short chain esters such as ethyl acetate or propyl acetate
Transdermal delivery of aromatic tetra-amidines for anticancer activity
1994
80
IPP-lecithin gel of diclofenac and indomethacin
Enhanced efficacy of NSAIDs administered through topical route
1999
35
Phytosphingosine or sphingosine lecithin organogel comprising soy PC, IPP, ethanol, and water
Treatment of scars
2001
84
Soy lecithin-isopropyl myristate (IPM) organogel containing ketamine hydrochloride and amitryptiline hydrochloride
Enhance skin penetration and partitioning of the drugs into the skin layers
2002
87
Nicardipine lecithin-IPM organogel
Enhanced skin permeation across guinea pig and human skin
2002
96
Methimazole in LO gel
Significant percutaneous absorption of methimazole
2002
97
LO gel of cardiac glycoside digoxin
Topical administration of the compound in LO gel was found to be effective for the treatment of muscle spasm
2003
82
Cyclobenzaprin in lecithin organogel (lecithin 10%-30%, IPM 10%-30%, water 30%-60%)
Topical formulation for bruxism
2003
83
*IPP indicates isopropyl palmitate; PC, phosphatidylcholine; NSAIDs, nonsteroidal antiinflammatories; IPM, isopropyl myristate; and LO, lecithin organogel.
Table 4: Topical Delivery of Therapeutic Substances in Pluronic Lecithin Organogels (PLO gels)
PLO Gel Formulation
Applications
Reference
Ketoprofen PLO gel
Administration of ketoprofen in PLO gel offered convenience, produced fewer side effects, and alleviated pain in a specific location
48
PLO gel of diclofenac, ibuprofen, ketamine
? Randomized, placebo-controlled study on lateral epicondylites employing diclofenac in PLO gel reduced pain and increased functional status.
? Preparation also found to be effective treatment for osteoarthritis
49
PLO gel of ondansetrone
Ondansetrone in PLO gel exhibited dose-dependent attenuation of nociceptive and inflammatory effects of intradermally injected capsaicin in humans
50
Lecithin (20%-40% vol/vol) in isopropyl palmitate or isopropyl myristate containing suitable amount of pluronic and water with or without short chain alcohol
The components of PLO gel provide desired hydration state to the skin, thus effective in the treatment of eczema or psoriasis
51
Lecithin organogel in combination of
pluronic F-127 (poloxamer 407) solution/cyclobenzaprin
Effective formulation for topical treatment of carpal tunnel syndrome
85
PLO formulation of local anesthetics and nonsteroidal antiinflammatories (NSAIDs)
Rapid onset of action, associated with low side-effect profile
86
PLO gel containing extract of Arnica Montana in combination with opioid
Effective treatment for pain management
88
Soy lecithin (18%-32% vol/vol) in isopropyl palmitate and pluronic F-127 (10%-40%)/ketamine
PLO gel maximizes the effectiveness of the ketamine, effectively alleviates neuropathic, sympathetic, and myofacial pain
89
Isopropyl palmitate and Poloxamer 407 containing PLO gel of saw palmetto extract
Selective delivery of antiandrogens into the pilosebaceous units for the treatment of androgenic alopecia
90
Bromelain (15%) and capsaicin in PLO gel
Excellent matrix for topical delivery of macromolecule
91
Hormones (e.g. progesterone) in PLO gel
Transdermal delivery of hormone
93
Micronized testosterone in PLO gel
Systemic delivery of hormone
94
Fluoxetine hydrochloride incorporated in PLO gel
Systemic delivery of the compound in feline patients
95
Safety and Skin Compatibity Studies
Lecithin-based organogel systems, i.e., LO or PLO gels are composed of pharmaceutically approved (non-immunogenic and bio-compatible) excipients. However, the level of surfactant and organic solvents in lecithin organogels is fairly high. Therefore, it is important to consider the safety and irritancy of the formulation on prolonged use. In this context, skin (human skin) compatibility of the gels has been evaluated employing various techniques, before and after application with either IPP alone or with 200mM lecithin-IPP gel.33, 35 No significant alterations in the skin were apparent after three days and stratum corneum was still intact.
The irritation potential of LOs has been assessed by Dreher et al., by carrying out human skin irritation study.36, 37 For the same, acute skin irritation was tested in as many as 151 volunteers in a 48 hour patch test. Results of the study showed very low acute irritation potential of LOs, as only 1-2% of the total volunteers showed a very slight erythema. The cumulative irritation test was also performed in order to assess the safety of organogels on long-term application. The parameter “IT50” was used as an index for the safety level, which is the time of continuous exposure after which 50% of the population reached a cumulative irritation score of ? 5. Results indicated a very low cumulative skin irritation potential of LOs. A fairly high IT50 value (13 days) supports the suitability of LO-based gels as a topical vehicle for long term applications.
Table 5: Commercially Available Pluronic Lecithin Organogels. 101-105
Therapeutic Category
Therapeutic Agents
Antiemetics
Dexamethasone, dimenhydrate, scopolamine
Muscle relaxants
Cyclobenzaprine, baclofen, buspirone
Neuropathy drugs
Clonidine, capsaicin, amitryptiline, gabapentin, phenytoin,
NSAIDs
Diclofenac, ibuprofen, ketoprofen, indomethacin,
Systemic analgesics
Acetaminophen, hydromorphone, morphine sulfate
Systemic hormones
Progesterone, testosterone
4. CONCLUSION
In the field of topical drug delivery, LOs have emerged as one of the most potential carrier systems. In contrast to other lipid-based systems such as vesicular systems, (liposomes and niosomes), lecithin organogel systems may prove to have an edge in terms of efficacy, stability and most importantly, the technological feasibility. Moreover, the topical delivery of new biotech generated proteinaceous molecules in the protective non-polar microenvironment of these systems may help protect these sensitive macromolecules from degradation while their transport to the desired site. The efforts, hitherto made, have been successful in highlighting the prospects of these systems for diverse applications. Now what more is desired are the detailed investigations on the structural and functional aspects of these systems. The influence of the organogel components, such as co-surfactant, organic solvent or other additives and their concentration, on the kind of microstructures that get generated within the system as well as on the topical drug transport mechanism should be investigated. Development of standards for the raw materials as well as for the processed products also needs efforts. Thus, amidst the increasing opportunities and challenges, the LOs may prove to be highly promising systems in realizing the drug delivery objectives while scientists are desperately trying for more viable alternatives vis-à-vis existing carrier systems.
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