LECITHIN ORGANOGEL-BASED SYSTEM FOR TOPICAL APPLICATION OF KETOROLAC TROMETHAMINE

Among various nonsteroidal anti-inflammatory drugs (NSAIDs), ketorolac tromethamine has been widely used for post operative and emergency treatment of pain. However, it accompanies adverse side effects including gastrointestinal irritation when administered orally. Topical administration of ketorolac offers the advantage of enhanced drug delivery to the affected sites with a reduced incidence of gastrointestinal side effects. However, as skin is an exceptionally effective barrier to most chemicals, very few drugs can permeate it in amounts sufficient to deliver a therapeutic dose. Therefore, systems that make the skin locally more permeable and thereby enable transdermal delivery are of great interest. Lecithin organogels are an example of such systems in which solutions of lecithin in organic solvents can be transformed into transparent gels by addition of a critical amount of water. The main objective of this study was to investigate lecithin organogels as carriers for topical application of ketorolac tromethamine. In this research, phase studies were carried out to obtain the concentration of components for the existence range of organogel and the effect of these additives on release rate of ketorolac was also evaluated through the artificial membranes and guinea pig skin. As the lecithin concentration was increased from 40 to 50 and then 60% w/w in formulations, a significant decrease in ketorolac release was obtained. A significant increase in drug release was also observed in formulations containing 6.5% w/w of ketorolac compared to those containing 1 % w/w of the drug. Increasing the water content of the organogels also resulted in an increase in ketorolac release. The optimum formulation of the organogel composed of 40% lecithin, 60% IPM containing 0.6% w/w of water and 6.5% w/w of ketorolac

enhanced drug delivery to the affected sites with a reduced incidence of gastrointestinal side effects. However, as skin is an exceptionally effective barrier to most chemicals, very few drugs can permeate it in amounts sufficient to deliver a therapeutic dose. Therefore, systems that make the skin locally more permeable and thereby enable transdermal delivery are of great interest. Lecithin organogels are an example of such systems in which solutions of lecithin in organic solvents can be transformed into transparent gels by addition of a critical amount of water. The main objective of this study was to investigate lecithin organogels as carriers for topical application of ketorolac tromethamine. In this research, phase studies were carried out to obtain the concentration of components for the existence range of organogel and the effect of these additives on release rate of ketorolac was also evaluated through the artificial membranes and guinea pig skin. As the lecithin concentration was increased from 40 to 50 and then 60% w/w in formulations, a significant decrease in ketorolac release was obtained. A significant increase in drug release was also observed in formulations containing 6.5% w/w of ketorolac compared to those containing 1 % w/w of the drug. Increasing the water content of the organogels also resulted in an increase in ketorolac release. The optimum formulation of the organogel composed of 40% lecithin, 60% IPM containing 0.6% w/w of water and 6.5% w/w of ketorolac tromethamine showed the highest drug release rate. Moreover, the viscosity of the different formulations and their rheological behavior were also determined. All formulations showed a slight rheopexy behavior rheogram. It was found that increase in lecithin concentration resulted in an increase in the viscosity of the organogel.
Overall, the results have suggested that ketorolac tromethamine could be incorporated with high concentrations into lecithin organogels which makes them interesting for use as a drug delivery vehicle for water soluble drugs.

Definition of Microemulsions
The microemulsion concept was introduced as early as the 1940s by Hoar and Schulman who generated a clear single-phase solution by titrating a milky emulsion with hexanol. However, the microemulsion definition proposed by Danielsson and Lindman in 1981 who stated a microemulsion as "a system of water, oil and amphiphile which is a single phase optically isotropic and thermodynamically stable liquid solution."

Emulsion versus Microemulsion
Recognizing the differences between an emulsion and a microemulsion is important. The major differences between the two are shown in Table 1 (Tenjarla, 1999). The transparency of microemulsions arises from their small droplet diameter, typically less than 140 nm. Such small droplets produce only weak scattering of visible light when compared with that from the droplets (1-10 µm) of emulsions. The interfacial tension in a microemulsion is very low compared to that in an emulsion.
This low interfacial tension leads to the spontaneous formation of the microemulsion, the small droplet size of the dispersed phase, and the thermodynamic stability of the microemulsion system. From the pharmaceutical manufacturing viewpoint, a microemulsion is very attractive compared with an emulsion. For an emulsion, several factors have to be considered when scaling up an optimum formulation to a manufacturing batch. These include scale-up equipment, compositional changes, only mild agitation, many of these factors are avoided in case of their preparation (Tenjarla, 1999;Attwood, 1994).

Structure of Microemulsions
A microemulsion can be one of the three types: (1) oil-in-water (o/w), in which water is the continuos phase; (2) water-in-oil (w/o), in which oil is the continuos phase; and (3) bicontinous, in which approximately equal volumes of water and oil exist (Figure 1, Tenjarla, 1999 (Lawrence et al. 2000). HLB indicates the surface activity of a species based on its molecular constitution. The simplest presentation of the structure of microemulsions is the droplet model in which microemulsion droplets are surrounded by an interfacial monolayer consisting of both surfactant and cosurfactant molecules. The orientation of the amphiphiles at the interface will, of course, differ in o/w and w/o microemulsions. As shown in Figure 1, the hydrophobic portions of these molecules will reside in the dispersed oil droplets of Oil Water-in-Oil Oil-in-Water Bi continuous Water FIGURE 1. STRUCTURE OF MICROEMULSIONS (Tenjarla, 1999) o/w systems, with the hydrophilic groups protruding in the continuos phase, while the opposite situation will be true of w/o microemulsions.

Stability of Microemulsions
Since microemulsions have a very large interface between oil and water because of the small droplet size, they can be only thermodynamically stable if the interfacial tension is so low that the positive interfacial energy can be compensated by the negative free energy of mixing. The role of surfactant in the system is thus to reduce the interfacial tension between oil and water. It is generally not possible to obtain this low interfacial tension with a single surfactant; the required low interfacial tension is achieved by adding a second surfactant, called a cosurfactant. Typical cosurfactants are short or long-chain alcohols, glycol, or polyglycerol derivatives (Attwood, 1994).
When a surfactant is added to a mixture of two immiscible phases, its molecules migrate to the interface, which results in lowering of the interfacial tension. When the surfactant occupies the entire interface between the immiscible liquids, adding more surfactant results in micelle formation, and there is no further decrease in the interfacial tension . Under these conditions, adding a second surfactant will further reduce the interfacial tension, resulting in a thermodynamically stable microemulsion.
The surfactant preferably should exhibit low solubility in the aqueous and nonaqueous phases of the microemulsion and should be adsorbed at the water-oil interface. The cosurfactant is also amphiphilic with an affinity for both the oil and aqueous phases and partitions into the surfactant interfacial monolayer present at the oil-water interface. In most cases, single-chain surfactants alone are unable to reduce the oil-water interfacial tension sufficiently to enable a microemulsion to form. A number of double chain surfactants and a few of nonionic surfactant such as bis (2-ethylhexyl) sodium fosuccinate (AOT) and lecithin are able to form microemulsions without the aid of cosurfactants (Lawrence et al., 2000;Bhatnagar et al., 1994).

Pseudo-ternary Phase Diagram
Generally, a pseudo-ternary phase diagram is constructed to determine the composition of polar, nonpolar, and surfactant phases that will yield a microemulsion.
For simplicity, the microemulsion is assumed a three-component system: water, oil, and a surfactant mixture. Any combination of these three components can be plotted as a percent on pseudo-ternary phase diagram (Tenjarla, 1999). Following is the rules relating to triangular pseudo-ternary phase diagrams: 1. Each comer of the triangle represents 100% of one of the components.
2. The points on the three lines joining the comer points represent two component systems of the three possible combinations.
3. Any line drawn through the apex points to a point on the opposite side will have a constant ratio of two of the components.
4. Any point on a line parallel to a side of the triangle has a constant proportion of one of the three components.
5. Any point inside the triangle represents all possible combinations of each component.

Determination of the Existence of a Microemulsion Region
The existence of a microemulsion region can be determined as follows: 1. Prepare a mixture of oil and surfactant blend at a predetermined ratio.
2. Slowly titrate the oil-surfactant mixture with the aqueous phase with continuos mixing. After each addition of the aqueous phase, observe the resulting system for clarity, viscosity, and stability.
3. Upon adding the aqueous phase, the system will clear (beginning of the microemulsion region), on continued titration with the aqueous phase, the system will become cloudy (end of the microemulsion region). The percent of the oil, surfactant, and the aqueous phase at the beginning and end of the microemulsion region are noted.
4. Repeat the whole procedure with a different oil-surfactant mixture ratio. Again, the percentages of the three components are determined at the beginning and end of the microemulsion region.
5. The various points at which the microemulsion regions form and end are connected on a pseudo-ternary phase diagram. The area enclosed by lines connecting the points represents the microemulsion region of the system (Attwood, 1994).

Choice of Microemulsion Components
Different types of aqueous and nonaqueous solvents and surfactants can be used to prepare a microemulsion formulation. A few examples are listed below: • Nonaqueous phase: Vegetable oils, synthetic oils, triglycerides, esters of fatty acids and so forth.
• Aqueous phase: Water, sodium chloride solution, buffers and so forth, or a combination of these.

Pharmaceutical Microemulsions
The selection of components for microemulsions suitable for pharmaceutical use involves a consideration of their toxicity and, if the systems are to be used topically, their irritancy and sensitizing properties. Importantly, in some cases nonionic surfactants are able to form microemulsions without the need for cosurfactant. This is helpful as it reduces the complexity of the phase behavior, and eliminates the requirement for inclusion of medium chain alcohols, since these cosurfactants have a poor toxicity profile and their evaporation can destabilize the system (Lawrence et al., 2000). Furthermore, the insensitivity of nonionic microemulsions to pH and ionic strength changes represents an added benefit. Although many nonionic surfactants have suitable properties for topical administration, their potential use in microemulsions use for oral or parenteral administration is very limited (Attwood, 1994). However, one of the problems associated with the use of microemulsions for topical drug delivery is the difficulty of applying these vehicles to the skin because of their fluidity.

Lecithin as a Surfactant
Lecithin, a nontoxic, naturally occuning biological surfactant, is a major component of membrane lipid. When administered in optimum amounts, it does not have a toxicity and sensitivity problems associated with most other surfactants. Hence, it is the ideal surfactant choice for preparing pharmaceutically acceptable microemulsions (Attwood, 1994). The characteristic solution properties of lecithin are: • Strong hydrophobicity resulting from the two long hydrocarbon chains • Strong hydrophilicity because of the zwitterionic polar head groups that are strongly hydrated and have dipole moments • Good balance between hydrophilic and lipophilic properties, with slight partiality to a lipophilic site

Lecithin Organogels
The first description of the lecithin organogels was given by Scartazzini and Luici in 1988. They found that an addition of trace amounts of water into nonequeous solutions of lecithin caused an abrupt rise in the viscosity, producing a transition of the initial non viscous solution into a jelly-like state.

Lecithin Organogel Components
Lecithin is a trivial name for 1, 2-diacyl-sn-3-phophocholine. Its structural formula is shown in Figure 2 (Shchipunov, 2001). It belongs to a biologically essential class of substances termed phosphoglycerides or phospholipids. They form the lipid matrix of biological membranes and play a key role in the cellular metabolism. As a Fatty acid residues Polar Region Nonpolar Region  (Shchipunov, 2001) biocompatible surfactant, it is widely used in every day life, including human and animal food, medicine, cosmetics and manifold industrial application.
The second component is an organic solvent, in which lecithin is capable of forming the organogel. Organic solvents could be linear, branched and cyclic alkanes, ethers and esters, fatty acids and amines.
The third component crucial for the organogel formation is water. This polar solvent is added in trace or small amounts that depend on the organic media. Water can be substituted for polar organic substances as glycerol, ethylene glycol and formamide (Shchipunov, 1995). Interest in the physical organogel field has increased with the discovery and synthesis of a number of substances able to gel organic solvents. Examples of such organogelators include, D-homosteroidal nitroxide (SNO), bis (2-ethylhexyl) sodium fosuccinate (AOT), lecithin, 2,3-bis-n-decyloxyanthracene (DDOA), and some ll azobenzene cholesterol derivatives. These organogels exhibit interesting properties such as the ability to solublize guest molecules, uses for purification and separation purposes and as transdermal delivery vehicles .

Molecular Model of Organogels
The initially spherical reverse micelles that are formed by lecithin molecules in a nonpolar organic solution transform into cylindrical ones, once water has been added. This was established with the help of light scattering and small angle neutron scattering techniques by Luisi and Schurtenberger in 1990. This one-dimensional growth of micelles is caused by the formation of hydrogen bonds between water molecules and phosphate groups of lecithin molecules so that two adjusting lecithin molecules are bridged together by one water molecule. IR and NMR spectroscopies showed that water molecules could interact simultaneously with phosphate groups of neighboring lipid molecules via hydrogen bonding, acting as a bridge between them (Shchipunov et al. , 1995). In this case, solvent molecules and lecithin phosphate groups can arrange in such a way that a hydrogen-bonding network will be formed. A possible arrangement is schematically shown in Figure 3 (Shchipunov et al., 1995).
The increase of water amount results in the formation of long tubular and flexible micelles. These so-called polymer-like, wormlike or spaghetti-like micelles can be entangled and therefore build up a transient three-dimensional network that is responsible for the viscoelastic properties of the lecithin organogels. Figure 4 represents the structure of lecithin reverse micelles as a function of added water (Hinze et al., 1996). At the critical concentration of water, the network shrinks and the  (Schurtenberger et al., 1990).
A series of polar solvents have been studied to determine how their nature influences the formation of jelly-like hydrogen binding network in lecithin solutions.
It has been established (Shchipunov et al., 1995) that glycerol, formamide and ethylene glycol, in addition to water, have the ability to induce organogel formation in the following order: glycerol> water> formamide> ethylene glycol. These polar solvents tend to be located in the most polar moiety of lecithin near the phosphate group. It has been inferred from the results that the organogel formation is sensitive to the structure of polar solvents, and in turn it should be sensitive to their physicochemical properties.  (Hinze et al., 1996)

Rheological Properties of Organogels
The transition from a low-viscous nonaqueous lecithin solution demonstrating Newtonian behavior to a jelly-like one with Maxwell rheology is caused by the addition of small amounts of polar additives. The transition can be clearly seen by a sharp increase in viscosity if a certain concentration of polar additive has been added (Shchipunov et al., 1999). Further addition of the polar additive results in a maximum of viscosity at a certain concentration. Thereafter a separation of the homogenous organogel into a two-phase system consisting of a low viscous fluid and a compact organogel occurs at a critical concentration. In other words, the viscosity depends on the molecular weight or the micellar length (Kantaria et al., 1999;Bhatnagar et al., 1994).

Application of Lecithin Organogels
Organogels have received a great attention in recent years for various applications, including topical application of drugs. Several mechanisms have been proposed to explain the advantages of organogels for the transdermal delivery of drugs. First, a large amount of drug can be incorporated in the formulation due to the high solubilizing capacity. Second, the permeation rate of the drug from the organogel may be increased, since the affinity of a drug to the internal phase in organogel can be easily modified to favor partitioning into stratum corneum, using different internal phase, changing its portion in organogel or adjusting its property. Third, the surfactant and organic solvent in the organogel may reduce the diffusional barrier of the stratum corneum by acting as permeation enhancers (Rhee et al., 2001).
The existence of microdomains of different polarity within the same singlephase solution enables both water-soluble and oil-soluble drugs to be solublised. The likely preferred sites of incorporation of a lipophilic, water-insoluble drug into an o/w microemulsion organogel are the disperse oil phase and/or hydrophobic tail region of the surfactant molecule, while a water-soluble drug would be most likely to be incorporated into the dispersed aqueous phase of a water-in-oil droplet (Trotta et al., 1997).
Use of w/o microemulsion organogel for oral or parenteral drug delivery is complicated by the fact that they are destabilized to a much greater extent when diluted by an aqueous phase. This is due to the increase in the volume fraction of the aqueous phase which increases the ratio of water to surfactant leading to droplet growth and eventually percolation (Attwood, 1994).

Topical Application of Drugs
Skin has become the subject of much study in the pharmaceutical field because of its role as a route of topical application (Dreher et al., 1996). Recent developments in transdermal drug delivery systems have been extensively studied as drug delivery methods showing promising topical efficacy. However, the stratum comeum in skin provides an effective impermeable barrier to the pecutaneous penetration of topically applied substances. In order to extend the range of drugs which can be administered via the skin and to enhance the effects of locally acting drugs, it is necessary to include penetration enhancers in formulations (Yokomizo, 1996). Generally speaking, since penetration enhancers cause skin problems such as erythema and are mitogenic stimulators there is a need for enhancers which do not stimulate and which are safe for skin. Phospholipids such as lecithin are a kind of penetration enhancers that directly influence the lipid bilayer of the cell membrane in the stratum corneum. They slightly disorganize the structure of the skin, and thus, permit the permeation of drugs. It is possible that this disorganization is due to interaction between these lipids and the phospholipids of the skin.

Drug Release from Organogels
The release rate of drugs in general from organogel systems depends on the drug partition coefficient, drug solubility in the oil and aqueous phases, dispersed droplet size, phase volume ratio, viscosity and specific drug-excipient interaction.
Small droplet size speeds up the drug release and has superior shelf stability (Cordero et al., 1997;Rhee et al., 2001). Delivery of a drug from an organogel is also directly proportional to the concentration of the drug. The intensity of drug partitioning into stratum corneum depends mainly on the lipophilicity of the drug used. Usually, the drug from the external phase is released on the surface of the membrane. Following this, drug from the internal phase partitions into the external phase to maintain the equilibrium. Therefore, there are different partitioning processes occurring: between the internal and external phases of the organogel, and between either the internal or the external phase of the organogel and the skin. Drug transport may be controlled by any of these processes, and the thermodynamic driving force for release will reflect the relative activities of the drug in the different phases (Delgado-Charro et al., 1997).

Ketorolac Tromethamine
Ketorolac Tromethamine (KT), a potent nonsteroidal anti-inflammatory drug is practically used for the postoperative and emergency treatment of pain. Figure 5 represents the chemical structure of KT (Quadir et al., 2000). However, it has side effects including GI irritation when administered orally. One promising method is to administer the drug via the skin. Novel prepared lecithin organogels incorporated with ketorolac are promising candidate for new drug delivery systems.  , 1992). Some of the obtained solutions were clear, others were cloudy, but the latter also became clear after addition of a minimal amount of water. The formation of the gels, after the addition of the water by a micropipette syringe, took place within 30 seconds. The drug-containing gels were prepared by dissolving KT into the water, and then adding the aqueous solution of KT into the mixture of lecithin/ IPM.

New Method of Preparation
In this method, the drug-containing gels were prepared by first dissolving KT into the solution of lecithin in organic solvent and then adding water to induce gelation. To facilitate the dissolution and obtain a homogenous mixture of dissolved components, the mixtures were heated for a very short time with constant stirring until solubilisation of the drug was completed. The dissolution was performed by means of a magnetic stirrer. Agitation was then stopped and the samples allowed to cool and set to a gel at room temperature. Formulations gave clear, homogenous, nonbirefringent gels.

Construction of Phase Diagram and Formulation of Ketorolac Organogels
Samples Initially, upon adding the aqueous phase, the mixture was cloudy. On continued addition, the system cleared, which indicates the beginning of the organogel region.
Upon the continued addition of the aqueous phase, the system eventually will become turbid again, indicating the end of the organogel region. The various points at which the organogel region forms and ends will be connected on a pseudo-ternary phase diagram. The area enclosed by lines connecting the points will represent the organogel region of the system. Based on these results, appropriate concentration ranges of components were used in the preparation of organogels containing ketorolac. The detailed composition of different preparations is given in Tables 2, 3, 4, 5, 6 and 7.

Release Data Analysis
The cumulative amount of ketorolac permeated through guinea pig skin or synthetic membranes was plotted as a function of time. The slope and intercept of the linear portion of the plot was derived by regression. The release rate (µg/cm 2 /h) was calculated as the slope and the intercept on the X-axis was taken as the lag time (h).
All release studies were the average of six individual cells.

Spectrophotometric and HPLC Analysis of Ketorolac
The amount of ketorolac released into the receptor medium was determined with either a spectrophotometric or HPLC method. For those samples analyzed by spectrophotometer, the UV detector was set at the specific absorbance wavelength (322 nm) for KT and concentrations were determined from a calibration curve obtained with known amounts of drug under identical analytical conditions.
An HPLC method was also utilized when guinea pig skin was used as a membrane for permeation studies. In this case, a C-18 column (3.9 mm i.d. x 300 mm) was eluted at 37 °C with a mobile phase consisting of acetonitrile-phosphoric acid solution (1.3 mM, pH 3.02) with a ratio of 34: 66 (v/v) at a flow rate of 1.5 ml/min and injection volume of 20 µl (Quadir et al., 2000). The retention time of ketorolac was 10 minutes and the detection wavelength was set at 322 nm. The concentration of KT was determined by comparing the absorbance of the unknown from a calibration curve. All operations were carried out at room temperature.

Preparation of Synthetic Membrane and Guinea Pig Skin
Cellulose acetate and silicone elastomer membranes soaked in distilled water for 24 h were used as artificial membranes. For guinea pig skin the whole skin was used as experimental skin.

Viscosity Measurements
The viscosity of the lecithin/ IPM/ water system depends on the amount of lecithin and added water into the organogel. An attempt was therefore made to observe the effect of added water and lecithin on the viscosity of the system. Viscosity of each sample was measured, using both cylindrical and cone & plate viscometers at a controlled temperature (25 °C).

Statistical Analysis
All the release experiments were repeated six times and their mean values with standard deviation are presented. A one-way ANOV A was used to test the statistical difference in the release profile between organogels of different compositions. The multiple comparisons within the formulations were also determined. Differences were assumed to be significant at p< 0.05.

Organogel Preparation
Poorly purified lecithin did not possess gel-forming properties. When synthetic lecithin containing residues of saturated fatty acids were examined, the organogel formation was not observed. The gelation took place only when a soybean lecithin (Epikuron 200) containing at least 95% phosphatidylcholine was used.

Phase Diagram Studies
The construction of a phase diagram made it easy to determine the concentration range of lecithin, IPM, KT and water for the existing range of organogels. Figure 8 shows the phase diagram, constructed to determine the optimum formulation of organogel. As shown in this figure, organogels exist in a narrow water concentration region. Decrease of viscosity, cloudiness and two-phase system appearance occurred at water excess. This figure shows the existence of the organogel occurred along the lecithin/IPM axis, where its extent increased as the weight percent of lecithin increased. Compared to the phase diagram constructed in the absence of KT, a relatively large gel region was observed when KT solution was incorporated into the organogel.
No significant differences in phase behavior were noted when altering the concentration of KT solution from 2.5 to 5 and then 10% w/v (Figures 9, 10, and 11).
However, a small decrease in the extent of the gel region was observed when 50% w/v of the drug solution was incorporated into the system ( Figure 12).
The phase diagram resulting from the new method of preparation showed a smaller existence area of organogel compared to those from the old method ( Figure   13). However, by using the new method of preparation it is possible to incorporate a higher amount of drug into the organogel. In this case, for each of the organogel samples, up to 6.5% w/w of KT could be dissolved compared to 1 % w/w in case of the old method. The detailed composition of eighteen different organogels is shown in   0.1 6.5 0.25 6.5 0.5 6.5 0.6 6.5 0.7 6.5 0.8 6.5 0.1 6.5 0.25 6.5 0.5 6.5 0.6 6.5 0.7 6.5 0.8 6.5 0.1 6.5 0.25 6.5 0.5 6.5 0.6 6.5 0.7 6.5 0.8 6.5

Effect of Membrane on KT Release from Organogels
Release studies were performed using, both cellulose acetate and silicone elastomer in order to find out if the release rates were influenced, by different artificial membranes. A significant ( p< 0.05) decrease in KT release was obtained when using silicone as a synthetic membrane. The release rate with the cellulose acetate membrane was -3 times (22.746 µg/cm 2 /h) higher than with the silicone membrane (7.6779 µg/cm 2 /h). This may be due to the differences in molecular weight cut-offs (MWCO) between cellulose acetate (3,500 Dalton) and silicone elastomer membrane.
As the drug molecular weight approaches the MWCO, the diffusion through the membrane slows dramatically.
The plot of cumulative release of KT through both membranes per unit area versus time is given in Figures 14, and 15. The effect of membrane on the release rate of KT from lecithin:IPM (40:60) containing 0.1 % w/w of water and 1 % w/w of KT is shown in Figure 16 (The experiment was done up to 10 hours when silicone elastomer was used as a membrane).

Formulation Effects
It was found from this study that KT release from organogels was highly variable and extremely dependent upon following factors: • KT concentration • Lecithin concentration • Water concentration

Membrane from Organogels with Different Compositions
The effect of the concentration on drug release rate from lecithin:IPM ( 40:60) containing 0.1 % water and both 1%and6.5% w/w of KT was evaluated. A significant ( p< 0.05) increase in drug release was obtained in formulations containing 6.5% w/w of KT compared to those containing 1 % w/w of the drug. The release rate of the formulation containing 6.5% KT was -10 times (223.12 µg/cm 2 /h) higher than the one containing 1 % of the drug ( in Figure 19 (The experiment was done up to 12 hours when the formulation containing 6.5% w/w of KT was used).
The data revealed that there is a positive correlation between drug concentration and release rate of the drug due to the increase in the thermodynamic activity. In this case, thermodynamic activity of the drug increases with concentration Similar results were obtained using guinea pig skin with the same formulation.
There was a significant ( p< 0.05) increase in KT release from organogels containing 6.5% w/w of KT compared to 1 % w/w of the drug.

Acetate Membrane from Organogels with Different Compositions
The effect of the organogel water concentration on the release rate of KT from different formulations containing 6.5% w/w of KT was also determined. While each of the organogels evaluated had the same ratio of lecithin/ IPM, differences in water concentration caused the release rate of KT to vary.   made the additional water and therefore, KT available within the system for partitioning into the membrane. A decrease in release rate of the drug at higher concentration of water (0.7% and 0.8% w/w) was observed, which suggests that at this concentration of water the three-dimensional network shrinks and organogel region ends. The same result was found for lecithin:IPM (50:50) and (60:40) except for the lowest release rate of KT, which happened at 0.25% w/w of water concentration. This finding is confirmed by Osborne et al., 1991

CONCLUSION
As shown in Figure 41, among all the different organogel formulations tested, Formula 4, which is composed of 40% lecithin, 60% IPM containing 0.6% w/w of water and 6.5% w/w of ketorolac tromethamine showed the highest release profile.
This formulation is the most desirable one based on the in vitro release studies. The mean cumulative amount of ketorolac from this optimum formula was 2555.757 ±192.55 (µg/cm2).
Our study demonstrates that lecithin organogels are promising candidates for topical application of KT since they reduce the possibility of GI irritation, and side effects associated with oral administration of the drug. Other advantages of these organogels arising from their solubilization capacity, transparency, high thermodynamic stability and simplicity of manufacture. They have the ability to solubilize guest molecules of different chemico-physical properties (ware-insoluble, amphiphilic or water-soluble compounds). The transparency of organogels enables them to be visually assessed for microorganism growth and presence of undissolved drug. Their transparency is also of benefit in topical preparation when clear systems are more aesthetically pleasing. They are quickly absorbed by the skin without greasy shine. There is no significant change in the viscosity, color or appearance of organogels after a very long time at room temperature. Organogels are isotropic and thermoreversibe. At temperature > 40 °C, they become liquids with much lower viscosity, and high viscosity gels are again formed by cooling. The formation of organogels requires only the most basic mixing equipment. Their manufacture is not