Topical Delivery of Flurbiprofen from Pluronic Lecithin Organogel

1. Elmas M, Trans B, Kaya S, Bas AL, Yazar E, Yarsan E. Pharmacokinetics of enrofloxacin after intravenous and intramuscular administration in angora goats. Can J Vet Res 2001;65:64-7. 2. Lizondo M, Pons M, Gallardo JE. Physicochemical properties of enrofloxacin. J Pharm Biomed Anal 1997;15:1845‐9. 3. Zhao L, Li P, Yalkowsky SH. Solubilization of fluasterone. J Pharm Sci 1999;88:967-9. 4. Millard JW, Alvarez-Nunez FA, Yalkowsky SH. Solubilization by cosolvents. Establishing useful constants for the log-linear model. Int J Pharm 2002;245:153-66. 5. Strickley RG. Solubilizing excipients in oral and injectable formulations. Pharm Res 2004;21:201-30. 6. Saha RN, Sanjeev C, Priya KP, Sreekhar C, Shashikanth G. Solubility enhancement of nimesulide and ibuprofen by solid dispersion technique. Indian J Pharm Sci 2002;64:529-34. 7. Ran Y, Zhao L, Xu Q, Yalkowsky SH. Solubilization of cyclosporin A. AAPS Pharm Sci Tech 2002;2:2. 8. Seedher N, Bhatia S. Solubility enhancement of cox-2 inhibitors using various solvent systems. AAPS Pharm Sci Tech 2003;4:33. 9. Mall S, Buckton G, Rawlins DA. Dissolution behaviour of sulphonamides into sodium dodecyl sulphate micelles: A thermodynamic approach. J Pharm Sci 1996;85:75-8. 10. Rangel-Yagui CO, Pessoa A. Jr. Tavares LC. Micellar solubilization of drugs. J Pharm Sci 2005;8:147-63. 11. Torchilin VP. Structure and design of polymeric surfactant-based drug delivery systems. J Control Release 2001;73:137-72.

Topical drug treatment aims at providing high concentration of the drug at the site of application so as to avoid systemic adverse effects associated with oral administration of drug.Organogel is a vehicle base for the delivery of drugs through the dermal and transdermal route.Organogels are formed by specific kind of small organic molecules, which in many solvents very effectively get self assembled into three dimensional networks there by turning a liquid into a gel [1] .Its micellar structure can contain both water and oil soluble ingredients; it shows excellent drug permeability by diffusion through the lipid intracellular matrix and by slight disorganization of skin.Pluronic and lecithin have become very popular in the topical delivery of drugs.A number of studies have shown that pluronic lecithin organogels (PLOs) have the unique capacity to deliver the drugs through the skin [1,2] and particular medications such as NSAIDs, hormones, antiemetics, opoids and local anesthetics [3] to a specific site when other routes of administration are not viable.Flurbiprofen, a propionic acid derivative is effective antiinflammatory and analgesic recommended in the management of patients with osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.It has a logP/hydrophobicity 4.078, having half-life of 4.7-5.7 h and molecular weight of 244.261 g/mol.These properties make it a potential candidate for topical delivery.
Flurbiprofen and Soya Lecithin were received as gratis samples from FDC Ltd, Mumbai and Phospoholipid GmbH, Nattermannallee, Germany, respectively.Pluronic F-127 was procured from Sigma Aldrich Chemie GmbH, Steinheim, Germany.Isopropyl palmitate, polyethylene glycol-600, sorbic acid and potassium sorbate were supplied by Loba Chemie, Mumbai, India.All other chemicals were of analytical grade and used as received.
The various formulations of PLO [4,5] (Table 1) were developed with different compositions.Oil phase was prepared by mixing soya lecithin and sorbic acid in appropriate quantity of isopropyl palmitate.The mixture was kept overnight at room temperature in order to dissolve its constituents.Aqueous phase was prepared by dispersing weighed amount of Pluronic F-127 and potassium sorbate in cold water.The dispersion was stored in refrigerator overnight for effective dissolution of Pluronic F-127.The next day, active ingredient flurbiprofen was dissolved in polyethylene glycol-600 and mixed with the lecithin-isopropyl palmitate solution; polyethylene glycol-600 was used for solubilization of flurbiprofen.Finally, aqueous phase (70%) was slowly added in oil phase (30%) with stirring at 400 rpm using mechanical stirrer.
The organogels prepared were evaluated for appearance and feel psychorheologically, drug content and content uniformity at 247 nm in ethanol, pH, viscosity using Brookfield Viscometer and in vitro diffusion/permeation using Keshary-Chien diffusion cell.The drug content of different formulations of organogel was determined by taking a standard curve of flurbiprofen in ethanol.For this, accurately weighed 50.0 mg of drug was transferred in a 50 ml volumetric flask, dissolved in ethanol and volume was made up with ethanol.Two millilitres of the solution was pipette out and diluted to 100 ml with ethanol.Then aliquots were further diluted with ethanol to get concentration of 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20 μg/ml.Absorbance were recorded spectrophotometrically and standard curve of flurbiprofen in ethanol was plotted at λ max 247 nm.Further for determining drug content, each formulation (0.5 g) was taken in a 50 ml volumetric flask, diluted with ethanol and shaken to dissolve the drug in ethanol.The solution was filtered through Whatman filter paper No. 42, one ml of the above filtrate was pipette out and diluted to 10 ml with ethanol.The content of the drug was estimated spectrophotometrically by using standard curve plotted at λ max 247 nm.
To test the pattern of release of drug from formulations, in vitro diffusion studies [4,6,7] were carried out.The developed formulations were subjected to in vitro diffusion through dialysis membrane-70, with molecular weight cut off 12000-14000 D and dehaired abdominal skin of Wistar albino rats was used as a semi permeable membrane using modified Keshary-Chien diffusion cell.The receptor compartment was filled with saline phosphate buffer (0.2 M, pH 7.4) and methanol (90:10).Methanol was added in medium to maintained sink condition.The whole assembly was maintained at 37±1° and receptor solution was stirred with a magnetic stirrer at 100 rpm throughout the experiment.Aliquots (1 ml) were withdrawn at regular interval of 1 h for a period of 8 h and replaced with equal volume of fresh medium equilibrated at 37±1°.All the samples were suitably diluted with medium and analyzed spectrophotometrically at 247 nm for flurbiprofen content.Viscosities [4,6] of the formulated organogels were determined using Brookfield Viscometer with Spindle no.7 (Model: RV DV-E 230) at 25° with the spindle speed of 10 rpm.The pH of formulated organogels was determined using pH meter.The electrode was immersed in organogels and readings were recorded on pH meter.All the formulations showed drug content in the range of 96-99% indicating uniform distribution of drug throughout the base.
The viscosity of all the formulations was found to be in the range 2910-3455 poise.The increase in viscosity with increase in lecithin concentration is might be due to formation of complex network.The results revealed that maximum in vitro cumulative percent drug release of flurbiprofen in 8 h was observed from FL2 formulation.Further increase in concentration of lecithin decreased cumulative percent drug release which might be due to extensive formation of network like structure with very high viscosity.Also from the in vitro diffusion studies it was found that the permeation of flurbiprofen through dialysis membrane-70 (fig. 1) was more as compared to rat skin (fig.2).The pH of all the formulations was around the skin pH and found to be in the range of 5.9 to 6.5.All the formulations were smooth in feel and free from grittiness which increases the patient compliance.The data obtained is shown in Table 2. From above studies it may be concluded that formulation FL2, containing 3% lecithin is an effective formulation for topical delivery of flurbiprofen as it showed higher cumulative percent drug release and drug content.Imidazolinone ring system is of biological and chemical interest since long.The imidazolinones [1] are associated with a wide range of therapeutic activities [2][3][4][5][6][7] such as anticonvulsant, sedative and hypnotic, potent CNS depressant, antihistamine, antifilarial, bactericidal, fungicidal, antiinflammatory, MAO inhibitory, antiparkinsonian, antihypertensive and anthelmintic.Recently some new imidazolinone derivatives have been reported as antiinflammatory, herbicidal and hypertensive activities.Some workers have recognized 5-imidazolone as having anticancer activity [8] .The therapeutic importance of the compounds inspired us to synthesize some potential imidazolinones [9][10][11][12][13] .
Desai et al. [14] have synthesized 4-benzylidene-2-phenyloxazole-5-one based on the methods descried in the literature which is a special type of Perkin condensation in which reaction between aldehyde and benzoylglycine proceeds first followed by ring closer.It is observed that aldehyde condenses under the influence of a base with the reactive methylene group in the azalactone which is formed by the dehydration of benzoylglycine, when the latter reacts with Ac 2 O in presence of sodium acetate.In view of these observations, we have synthesized imidazol-5-ones (Scheme I, Table 1).