Sr. No.	PLO gel formulation	Applications	Reference
1.	Ketoprofen PLO gel	Offeres convenience, produced fewer side effects, and alleviated pain in specific location	51
2.	PLO gel of diclofenac, ibuprofen, ketamine	Reduces pain and increases functional status. Also effective in treatment for osteoarthritis.	52
3.	PLO gel of ondansetron	Exhibits dose dependent attenuation of nociceptive and inflammatory effect of intradermally injected capsaicin in humans	53
4.	Lecithin ( 20-40 % v/v) in isopropyl palmitate or isopropyl myristate containing suitable amount of pluronic and water with or without short chain alcohol	Provides desired hyration stete to skin. Effective in treatment of eczema or psoriasis.	54
5.	Lecithin organogel in combination with pluronic F- 127 (poloxamer 407) solution / cyclobenzaprin	Effective formulation for topical treatment of carpel tunnel syndrome	55
6.;	PLO formulation of local anaeshetics and non-steroidal anti-inflammatories ( NSAID’s)	Rapid onset of action with low side effects	08
7.	PLO gel containing extract of Arnica Montana in combination with opoid	Effective treatment for pain management	56
8.	Soy lecithin (18-32 % v/v) in isopropyl palmitate and pluronic F- 127 ( 10-40 % ) / ketamine	Maximizes effectiveness of ketamine. Effectively alleviates neuropathic, symphathatic, myofacial pain.	57
9.	Isoprypyl palmitate and poloxamer 407 containing PLO gel of saw palmetto extract	Selective delivery of antiandrogens into the pilosebaceous units for treatment of androgenic alopecia	58
10.	Bromelain (15 % ) and capsaicin in PLO gel	Exellent matrix for topical delivery of macromolecule	59
11.	Hormones (e.g. : progesterone) in PLO gel	Transdermal delivery of hormone	60
12.	Micronized testosterone in PLO gel	Systemic delivery of hormone	61
13.	Fluoxetine hydrochloride incorporated in PLO gel	Systemic delivery of compound in feline patients	64

What is PLO Base? :

The PLO base is composed of three main ingredients: Pluronic gel, lecithin and isopropyl palmitate. In general, a gel is a two-phase colloidal system containing a solid and a liquid phase (water in pharmaceutical gels). Gels formed with poloxamers (Pluronic) are liquid (sol) at cold temperatures and undergo a phase change (gel) when the temperature is elevated. For optimal efficacy, 20% w/w of Pluronic F127 retains the gel structure from 20 to 70°C. This characteristic makes it useful in pharmaceutical compounding because it can be drawn into a syringe for accurate dose measurement when it is cold. The degree of viscosity of the Pluronic gel is dependent on the ratio of Pluronic to water; the higher the Pluronic concentration, the higher the viscosity. Pluronic is a reverse thermal gel, and its viscosity increases with higher temperatures, such as from the refrigerator to room temperature to application to the human body at 98.6°F. Alteration of the component concentrations in any way may change the bioavailability of the active drug.⁸Some organic solvents may weaken the gel strength, or water-insoluble organic materials may increase the gel strength, while inorganic salts and strong electrolytes usually soften the gels. The incorporation of additional surfactants may weaken the gel strength by competing with the hydrogen-bonding lattice.⁹

Pluronic:

Pluronic (poloxamers) are bifunctional block copolymer surfactants consisting of ethylene oxide and propylene oxide terminating in a primary hydroxyl group. Pluronic gels are believed to be formed by hydrogen bonding in aqueous Pluronic systems, caused by attraction of the surfactant ether

oxygen atoms with water protons, making a high level of oxyethylation coupled with a high molecular weight.¹⁰

Lecithin:

Lecithin is a naturally occurring mixture of diglycerides of stearic, palmitic and oleic acids linked to the choline ester of phosphoric acid, commonly called phosphatidylcholine. Lecithins vary greatly in their physical form, from viscous semiliquids to powders, depending upon their free fatty-acid content; are almost odorless; vary from brown to light yellow; decompose at extreme pH; are hygroscopic; and will oxidize, darken and decompose at high temperatures. Lecithin should be stored at room temperature and protected from light. Refrigeration may cause the material to separate. Since the success of any transdermal delivery system depends on its ability to penetrate through the stratum corneum layer, lecithin is added to this formulation. It has been shown that the improvement of skin permeation is related to both the solubilizing effect of the lecithin matrix and the penetration enhancing effect of lecithin itself.¹¹ Penetration enhancers could function by a number of mechanisms, including disorienting the lipid bilayer of the membrane or changing the solubility or dispersibility of the medicaments.^12,13

Isopropyl Palmitate:

Isopropyl palmitate acts as a solubilizing agent for lecithin and also as a nonoleaginous emollient with good spreading characteristics. It is a clear, colorless to pale yellow-colored, practically odorless viscous liquid that solidifies at less than 16°C. It should be stored in well-closed and light-resistant containers. The inclusion of isopropyl palmitate imparts the name organo to this product.⁹ A large variety 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.¹⁵Amongst the above, the fatty acid esters, i.e., IPM and IPP are of particular interest for topical applications of LOs.^{9, 14}

Method of preparation and Drug Incorporation:

Preparation of PLO:

The oil phase is prepared by mixing lecithin and isopropyl palmitate and allowing the mixture to stand overnight to ensure complete dissolution. The aqueous phase is prepared by adding pluronic F 127 to ice cold water, placing the mixture in a refrigerator and agitating periodically to ensure complete dissolution.¹⁶Sorbic acid at 0.2 % w/w is often added to the two phases as a preservative.¹⁷To prepare PLO , the oil phase is then mixed with the aqueous phase using a high shear mixing method, for example, using two syringes, connected by a luer lock for small volumes or by using an electronic pestle and mortar.⁵It is important that the aqueous phase is cold before mixing because an aqueous solution of pluronic F 127 is in the liquid state at a low temperature and gels at a higher temperature.

Incorporation of drugs in PLO:

Drugs may be incorporated within PLO either by dispersing the appropriate quantity of drug into pre-prepared PLO¹⁸ or, more commonly by dispersing the drug in either the oil phase or the aqueous phase, depending on drug solubility, before mixing the two phases.^19,20 Dispersion of the drug in the aqueous phase or oil phase may e conducted by first dissolving the drug in a small quantity of water for a hydrophilic drug,²⁰ or by mixing the drug with propylene glycol for lipophilic drugs to form a paste,^16,17 which is then mixed with the appropriate aqueous or oil phase.

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.^{4, 15, and 16}

a) 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.^4,15 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 then major driving forces for the self-assembly of organogelator molecules in the organic solvents.^{22,23,24,25,26} The knowledge of molecular packing within the organogel metwork has been obtained using scanning and transmission electron microscopies (SEM and TEM),⁴dynamic and static light scattering (elastic or quasielastic light scattering techniques QLS),^15,21,27-29 small-angle neutron scattering (SANS), small-angle X-ray scattering (SAXS) and atomic force microscopy (AFM).^15,21,30-33These 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.^33,34 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 “ξ”, the mesh size of the network (orthe number density of entanglements ‘ν’), diffusion coefficients and flexibility of the fibrous network etc., along with the structural features of the cross-sections of LOs.^{4,15, 31,
32, 35, 36} 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 fibres 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.

b) 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 rheological attributes and determined to be viscoelastic in nature.^37,38,25,40 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.²⁵ 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.^37, ^25,41,39 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.^15,21 Similarly, Schurtenberger et al.⁴² 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.

c) Phase transition temperatures:

The phase behavior of organogels is subjected to vary on changing temperature conditions.¹⁵ 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.⁴³It also reveals the microstructural 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.^43,44 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.^15,43 However, the “inverse flow method”, a simple technique based on visual observations has also been employed.⁴⁵

d) 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.⁴⁶have 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, 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.

Drugs used with PLO:

Table 1 shows the list of drugs used with PLO and their applications:

Clinical evidence for use:

In these clinical studies effects of the drugs measured, while in others, the plasma drug concentration was measured.^63-66 In addition the efficacy of PLO was assisted following a single application in some studies ^63-66 and after repeated applications in others.^62,67,68 Table: 2 shows the systematic studies of the efficacy of PLO.

In cats:

The studies in healthy cats showed that following a single topical application of a drug ( methimazole, fluoxetine, dexamethasone, amitriptyline or buspirone ) in PLO to the inner pinna, significant drug absorption into the systemic circulation did not occur and plasma drug concentrations were either low or undetectable.^63-66 On the other hand the retrospective study in cats suffering from hyperthyroidism showed that repeated application of methimazole in PLO, over a period of weeks and months, led to the resolution of many clinical symptoms and to a reduction in total thyroxine levels.⁶² It is possible that the latter results may be due to repeated application of the gel to the same skin site ( pet owners were not advised to apply the gel to the same ear or to change sides), which could have resulted in irritation of the skin and enhanced drug absorption through the breached skin barrier. Substantial skin irritation after application of PLO for several days has also been reported.⁶⁴ It is also possible that the clinical effects observed were due to oral ingestion of the PLO during grooming.

In man:

The in-vivo studies in man, where PLO was applied repeatedly, suggests that PLO may be beneficial as a delivery vehicle for local action.^67,68In these studies, diclofenac in PLO was applied over a number of weeks for the treatment of osteoarthritis of the knee or for lateral epicondylitis. Following application of PLO, patients experienced less pain^67,68 and increased wrist extension strength.⁶⁸ However drug levels in the blood were not measured and drug absorption into the systemic circulation cannot be assumed. In a third study, the efficacy of PLO as a transdermal delivery vehicle for ondansetron, following a single application was evaluated in 12 healthy human volunteers.⁶⁹ Although the gel was reported to be a good vehicle for ondansetron, it is difficult to evaluate the benefits of PLO from this study as the preparation of PLO was not described and instead an inappropriate reference³ was used to indicate the method of preparation. This same reference (which has results pertaining to the original lecithin organogel rather than to PLO) was again used inappropriately as a source which “proved” PLO gels to be efficient vehicles and which afforded local bioavailabilty.

CONCLUSION:

To summaries, PLO characterization is still needed. The few in-vivo studies conducted have shown that a single topical application in cats did not lead to significant absorption of the drug into the system circulation but repeated applications to the same skin site in man led to clinical effects. In practice, patients are normally advised to rotate skin sites when transdermal vehicles are applied to reduce the possibility of skin irritation. Thus further systematic, in vivo studies where PLO is applied repeatedly to both the same and different skin are still needed as well as research to assess drug concentrations in the blood, disease progression and regression, and skin irritation.

Table 2: Systematic studies of the efficacy of Pluronic Lecithin Organogel

Drug	Experimental Subjects	Study Details	Results
Methimazole⁶²	Cats suffering from hyperthyroidism, n = 13	Retrospective evaluation of cats suffering from hyperthyroidism repeatedly treated with methimazole in PLO	Resolution of clinical signs such as weight loss, inappetence, mental changes, vomiting, dry hair coat. Significant decrease in total thyroxine between pre-treatment and during treatment values.
Methimazole⁶³	Healthy cats, n = 6	Triple cross-over study to determine bioavailability of topically applied methimazole in PLO to cat pinnae compared with intravenous and oral administrations, after a single dose	Low to undetectable bioavailabilty following topical application in PLO. One cat achieved 100 % transdermal bioavailability compared with oral route.
Fluoxetine⁶⁴	Healthy cats, n = 4	Parallel study involving three groups of four cats to determine bioavailability, pharmacokinetics and safety of transdermal delivery of fluoxetine (5 mg/kg and 10 mg/kg) in PLO, and oral fluoxetine following a single dose.	Absorbed to some extent following topical application. Bioavailability of transdermal route was 10 % of that oral route.
Dexamethasone⁶⁵	Healthy cats, n = 5	Cross-over study to compare serum concentrations of dexamethasone after a single oral or topical application in PLO to cat pinna	No significant absorption following topical application. All values were below the detection limit of assay.
Amitriptyline and Buspirone⁶⁶	Healthy cats, n = 3	Cross-over study to compare absorption of amitriptyline and buspirone after a single oral or topical application in PLO to the cat pinna	Plasma concentrations of amitriptyline were below the limit of quantification but above the limit of detection. Plasma concentrations of buspirone were below the limit of detection.
Diclofenac⁶⁷	Patient suffering from osteoarthritis of knee, n = 74	Double-blind, randomised, placebo conrolled, parallel group design, two week clinical trial to assess the efficacy and safety of topically applied diclofenac in PLO, three times daily for two weeks, to treat pain associated with mild to moderate arthritis of the knee	Subjects experienced less pain and stiffness.
Diclofenac⁶⁸	Patient suffering from lateral epicondylitis, n = 14	Double-blind, randomised, cross-over study to determine effectiveness of diclofenac in PLO, applied three times daily for one week, as a treatment for lateral epicondylitis	Subjects experienced less pain. Average wrist extinction strength was also significantly greater.
Ondansetron⁶⁹	Healthy men, n = 12	To determine efficacy of PLO as a transdermal delivery vehicle for ondansetron. Capsaicin intradermally injected one minute later odansetron, in PLO, single application, to the skin surrounding the injection. Pain, hyperalgesia and inflammatory flare were assessed four minutes later.	Reduces pain, mechanical hyperalgesia and inflammatory flare induced by intradermally injected capsaicin in a dose dependent manner

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Received on 27.09.2008 Modified on 15.11.2008

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