The microemulsion systems

The microemulsion systems, o/w, composed of castor oil, sesame oil, arachis oil, olive oil, polysorbate 20, polysorbate 80, Tyloxapol, Carbomer 974P, carboxymethyl cellulose sodium, hydroexthylecellulose, glycerine, propylene glycol, sodium chloride and purified water, taken at various amounts and in various combinations, were tested in order to assess their physical-chemical compatibility. All ingredients of the microemulsions were physiologically acceptable. Microemulsions were evaluated for the different parameters to access the effect of processing parameters on the globule size formation and stability. The stable microemulsion system was obtained for the formulation in which castor oil and polysorbate 80 was used.. The following parameters were analyzed description, pH, osmolality, viscosity, specific gravity, globule size, polydispersity index (PDI) zeta potential, surface tension, assay, in vitro Drug Release. The study made it possible to select the most stable microemulsion system meeting the requirements of eye drops. Thus the proposed formulation and process were successfully developed and evaluated. KEYWORDS Microemulsion, Surfactant, Drug solubilizing agent, Homogenization, globule size INTRODUCTION Overview of Ophthalmic drug delivery Ophthalmic drug delivery is one of the most interesting and challenging endeavors facing the pharmaceutical scientist. The anatomy, physiology, and biochemistry of the eye render this organ highly impervious to foreign substances. A significant challenge to the formulator is to circumvent the protective barriers of the eye without causing permanent tissue damage. Development of newer, more sensitive diagnostic techniques and novel therapeutic agents continue to provide ocular delivery systems with high therapeutic efficacy. Potent immunosuppressant therapy in transplant patients and the developing epidemic of acquired immunodeficiency syndrome have generated an entirely new population of patients suffering virulent uveitis and retinopathies. Conventional ophthalmic solution, suspension, and ointment dosage forms no longer constitute optimal therapy for these indications. Research and development efforts to design better therapeutic systems particularly targeted to posterior segment are the primary focus of this text. The goal of pharmaco-therapeutics is to treat a disease in a consistent and predictable fashion. An assumption is made that a correlation exists between the concentration of a drug at its intended site of action and the resulting pharmacological effect. The specific aim of designing a therapeutic system is to achieve an optimal concentration of a drug at the active site for the appropriate duration. Ocular disposition and elimination of a therapeutic agent is dependent upon its physicochemical properties as well as the relevant ocular anatomy and physiology1. A successful design of a drug delivery system, therefore, requires an integrated knowledge of the drug molecule and the constraints offered by the ocular route of administration. The active sites for the antibiotics, antivirals, and steroids are the infected or inflamed areas within the anterior as well as the posterior segments of the eye. Receptors for the mydriatics and miotics are in the iris ciliary body. A host of different tissues are involved, each of which may pose its own challenge to the formulator of ophthalmic delivery systems. Hence, the drug entities need to be targeted to many sites within the globe. Historically, the bulk of the research has been aimed at delivery to the anterior segment tissues. Only recently has research been directed at delivery to the tissues of the posterior globe (the uveal tract, vitreous, choroid, and retina). Ophthalmic microemulsion For the treatment of different extra- and intra-ocular aetiological conditions such as glaucoma, uveitis, keratitis, dry eye syndromes, cytomegalovirus retinitis, acute retinal necrosis, proliferative vitreo retinopathy, macular degenerative disease, etc. a lot of lipophilic and poorly water soluble drugs have become available in recent years. However, most of the traditional ophthalmic dosage forms are clearly not only uncomfortable for the patient, but also not efficient in combatting some of the current virulent ocular diseases. Furthermore, in ophthalmology, the low viscosity topical formulations either in aqueous-based eye drops or in liquid retentive suboptimal forms are generally preferred to provide local drug concentrations in the precorneal or aqueous humor part of the eye. In the last decade, oil-in-water (o/w) type lipid emulsions, primarily intended for parenteral applications, have been investigated and are now exploited commercially as a vehicle to improve the ocular bioavailability of lipophilic drugs2, 3, 4. Figure SEQ Figure ARABIC 1 Anatomical structure of the human eye. Oil and water are immiscible. They separate into two phases when mixed, each saturated with traces of the other component5 . An attempt to combine the two phases requires energy input to establish water-oil contacts that would replace the water-water and oil-oil contacts. The interfacial tension between bulk oil and water can be as high as 30-50 dynes/cm6 . To overcome this, surfactants can be used. Surfactants are surface-active molecules. They contain water-loving (hydrophilic) and oil-loving (lipophilic) moieties7. Because of this characteristic, they tend to adsorb at the water-oil interface. If enough surfactant molecules are present, they align and create an interface between the water and the oil by decreasing the interfacial tension5. An emulsion is formed when a small amount of an appropriate surfactant is mechanically agitated with the oil and water. This results in a two-phase dispersion where one phase exists as droplets coated by surfactant that is dispersed throughout the continuous, other phase. These emulsions are milky or turbid in appearance due to the fact that the droplet sizes range from 0.1 to 1 micron in diameter6. As a general rule, the type of surfactant used in the system determines which phase is continuous. If the surfactant is hydrophilic, then oil will be emulsified in droplets throughout a continuous water phase. The opposite is true for more lipophilic surfactants. Water will be emulsified in droplets that are dispersed throughout a continuous oil phase in this case8. Emulsions are kinetically stable, but are ultimately thermodynamically unstable. Over time, they will begin to separate back into their two phases. The droplets will merge together, and the dispersed phase will sediment (cream) 6. At this point, they degrade back into bulk phases of pure oil and pure water with some of the surfactant dissolved in preferentially in one of the two5. From the extensive literature cyclosporine was selected for the study as it has poor water solubility and is highly lipophilic in nature. Cyclosporine is a white crystalline powder with chemical formula C62H111N11O12 and molecular weight of 1202.6. Cyclosporine is Soluble in ethanol and DMSO. Figure 1 Chemical structure of Cyclosporine MATERIAL AND METHODS Chemicals and reagents Cyclosporine API was received as gift sample from Concord biotech, India. Carbomer 974P was received as gift sample from Aqualon and Carboxymethylcellulose sodium and Hydroxyethylcellulose was received as gift sample from Ashland. Polysorbate 20 and Polysorbate 80 were purchased from Merck chemicals. Tyloxapol was received as gift sample from Amri renseller. All chemicals and reagents used were analytical grade unless otherwise indicated. Instrumentation A variety of techniques can be used to characterize microemulsions. In the present study, microemulsions were characterized using dynamic light scattering, polarized light microscopy, zeta potential, surface tension, pH, osmolality, viscosity, drug assay and in vitro drug release. The each technique used for the test parameter determination is given as below, Table SEQ Table ARABIC 1 List of instruments and techniques used Sr. no.Technique nameInstrument name and modelParameter tested1Dynamic light scatteringZetasizer nano ZS (Malvern)Globule size and polydispersity index2Polarized light microscopyMicroscope and TEMMorphology3Zeta potentialZetasizer nano ZS (Malvern)Zeta potential4Du Nouy ring methodTensiometer K100 (Kruss GmbH, Germany)Surface tension5pH measurement pH meter (Thermo)pH6Tonicity measurementOsmomter (Osmomat)Osmolality7Viscosity measurementBrookfiled viscometer (DV Pro)Viscosity8Drug assayHPLC (Agilent) with UV detectorAssay8DissolutionFranz diffusion cellIn Vitro drug release9High shear homogenizationHigh Shear mixer/homogenizer (Ultraturex IKEA)For primary emulsion formation10High pressure homogenizationHigh pressure homogenizer (Panda Nero Soavi)For microemulsion formation11AutoclavingAutoclave (Thermo)For steam sterilization Formulation development From the literature survey and understanding of the ophthalmic microemulsion, following types of the ingredients are required to form the stable microemulsion. Table SEQ Table ARABIC 2 Typical composition of ophthalmic microemulsion Sr. No.Ingredient Class1Active Pharmaceutical ingradient2Drug solubilizing agent (Oil base)3Surfactant4Tonicity modifier5Viscosity modifier6pH adjustment agent7VehicleCritical quality product profile Below table summarizes the quality attributes of ophthalmic emulsion and indicates which attributes were classified as drug product CQAs. For this product, physical attributes (e.g. pH, globules size distribution, viscosity, assay, related substances) are considered as critical. On the other hand, CQAs including identity, Osmolality, sterility which are unlikely to be impacted by formulation and process variables will not be discussed in detail in the pharmaceutical development report. However, these critical quality attributes (CQAs) are still target elements of the QTPP and are ensured through the product and process design and the control strategy. Table SEQ Table ARABIC 3 Quality attributes of ophthalmic emulsion Drug Product Quality AttributesTargetCriticalityJustificationDescription Homogenous emulsionYesNon homogeneity of emulsion indicate the instabilityIdentification Positive for APINoBoth the formulation and process unlikely impact the identityAssay 90-110 of label claimYesProcess may affect the assay value of the drug productDegradation Product As per ICHNoBased on the ICH limit.Globule Size Distribution Z (Average ) 100-200 nmYesSafety and efficacy of the emulsion dependent on the droplet size of the emulsion. Physical stability of the dispersed system is directly dependent on the droplet size.Viscosity 150 to 350 cpsNoViscosity of the attributes of grade, concentration and type of polymer used in the product. None of the process parameters will affect the viscosity of the emulsion formulation.pH 6.5 to 8.0NoNot critical because, the desired pH is adjusted using suitable pH adjusting agent.Osmolality 250-350 mOsml/kgNoNo change in the Osmolality value over the period of timeSterility Must be sterileYesMeet the requirement of sterile drug product Pre-formulation studies Solubility study of the Drug The solubility of Cyclosporine in various oils, surfactants and co-surfactants was determined. An excess amount of Cyclosporine was added to 5 ml of each selected oils and was shaken reciprocally at 25C and 60C for 24 hrs. After solubilization at both the temperatures, drug solutions were kept at room temperature for 1 month to study physical stability. Compatibility study with Surfactants Polysorbate 80, Polysorbate 20 and Tyloxapol are the most used and approved surfactant in ophthalmic and injectable formulations. These were used for the compatibility study with the drug in 12 ratios. The drugs were dispersed in Polysorbate 80, Polysorbate 20 and Tyloxapol. These were kept at 25C and 60C for 7 days and checked for the physical observations. Interaction study between oil solubilized API and surfactant The interaction between solubilized drug in oil and the emulsion forming agent surfactant is very crucial for stability of the microemulsion. Cyclosporine was dissolved in the oils viz. castor oil, arachis oil, sesame oil and olive oil. All of oil solubilized drug solutions were mixed with different surfactant in 12 ratios. These mixtures were kept at 400C for 30 days. Selection of Ingredients Selection and Optimization of Surfactant concentration Compatibility studies were carried out using Polysorbate 80, Polysorbate 20 and Tyloxapol. Based on the compatibility studies, all surfactant were used for further stability studies with below concentrations, Table SEQ Table ARABIC 4 Surfactant concentrations for compatibility studies SurfactantsSurfactant concentrationPolysorbate 800.5 , 1.0 and 1.5 Polysorbate 200.5 , 1.0 and 1.5 Tyloxapol0.5 , 1.0 and 1.5 Selection and Optimization of Viscosity modifier and Tonicity moodier Viscosity Modifier Viscosity modifier is used in ophthalmic solutions to increase their viscosity. This enables the formulation to remain in the eye longer and gives more time for the drug to exert its therapeutic activity or undergo absorption.Carbomer 974P, hydroxyethylcellulose MX grade, carboxymethylcellulose sodium 7MFPH, viscosity modifier agents were used for the study. Experiments were carried out using the all of the viscosity modifying and the below concentrations were used, Table SEQ Table ARABIC 5 Concentrations of viscosity modifier Tonicity modifier Based on the theoretical osmolality calculations below concentrations of tonicity modifier were used, Table SEQ Table ARABIC 6 Concentration of tonicity modifier Viscosity modifierTonicity modifier Concentration Sodium Chloride0.9Mannitol5Glycerin2.7Propylene Glycol1.1Selection of optimized formula Based on the experimental work carried to develop ophthalmic microemulsion, following formulae was selected for stability studies and complete evaluation. Table SEQ Table ARABIC 7 Proposed final formula of the Cyclosporine ophthalmic microemulsion Sl. No.IngredientsFormula AFormula BUOM1Cyclosporine0.050.05G2Castor oil1.01.0G3Polysorbate 801.01.0G4Glycerin2.702.70G5Carbomer 974P0.5-G6Hydroxyethylcellulose(MX)-0.25G7Sodium hydroxideQ.S to pHQ.S to pH-8Hydrochloric acidQ.S to pHQ.S to pH-9Purified waterQ.S. to 100mLQ.S. to 100mL-Above formulations were prepared with the optimized process parameters and were tested for the all physicochemical parameters. Microemulsion preparation Studies were performed on a laboratory scale with batch sizes ranging from 100 mL to 1000 mL. Cyclosporine was practically insoluble in purified water. Hence, the API is needed to dissolve oil under continuous stirring at elevated temperature. Once a clear solution is obtained, further processing is done. The brief process is given as below, Solubilization of drug in oil at elevated temperature. Transfer sufficient quantity of purified water in the compounding vessel. Add batch quantity of surfactant under continuous stirring. Pre-mix the surfactant solution and oil phase using overhead/magnetic stirrer. Set the high shear homogenizer at suitable parameters. Transfer the API/ oil in the surfactant solution under continuous stirring and high shear homogenization. Connect the High-pressure homogenizer with SS tank in the recirculation mode and continue homogenization of the emulsion at 50 to 80C. Continue the homogenization till the desired emulsion size attained. Polymer phase was prepared by dispersing Viscosity modifier in sufficient quantity of purified water under continuous stirring. Separately tonicity modifier is dissolved in sufficient quantity of purified water and added to the polymer phase from above step. Check and adjust the pH of the emulsion and adjust if required with NaOH or HCl solutions. Mix the above bulk emulsion Filter and transfer the microemulsion from step 8 to polymer excipient phase from step 12 under stirring. Make-up the volume of the batch to 100 of the batch size with purified water. Mix the emulsion under slow continuous stirring for suitable period of time. An outline of the manufacturing process unit operation is given in figure below, Figure SEQ Figure ARABIC 2 Typical Manufacturing process flow for microemulsion Process optimization Crude emulsion was subjected to the high shear homogenizer at different temperature as below, Table SEQ Table ARABIC 8 Different temperature setting for high shear homogenizer Trial No.TemperatureTime in minRPMC45RT102000D46400C102000C47500C102000C48600C102000C49700C102000C50800C102000 Based on the above experiments, following temperature and different RPM setting of high shear homogenizer were evaluated, Table SEQ Table ARABIC 9 Different RPM setting for high shear homogenizer Trial No.TemperatureTime in minRPMC5160-700C101000C5260-700C102000C5360-700C103000High pressure homogenization Objective of the high pressure homogenization is to achieve the desired droplet size of emulsion. At the end of primary emulsification, Panda, (Make Gea Niro Soavi) which is a high pressure system (upto 30,000 psi) was used to reduce the droplet size of the disperse system. Primary emulsion was pumped through the interaction chamber at very high pressure, as the coarse emulsion passes through the valves it experiences a combination of intense high shear and turbulent flow conditions. Internal force in turbulent flow along with cavitation is predominantly responsible for droplet size reduction in high pressure homogenizer. Reduction in the emulsion droplet size is a function of time. Primary emulsion was subjected to different settings of high pressure homogenization as per the below parameters, Table SEQ Table ARABIC 10 Different pressure setting for high pressure homogenizer Trial NumberC54C55C56High Pressure Homogenization pressure1000 Bar1250 Bar1500 BarTemperature60-700C60-700C60-700C Effect of temperature against the high pressure homogenization and following trials were carried, Table SEQ Table ARABIC 11 Different temperature setting for high pressure homogenizer Trial NumberC57C58C55High Pressure Homogenization pressure1250 Bar1250 Bar1250 BarTemperature25-350C45-550C60-700C Results Process optimization High shear homogenization The results of this process are given in the table below, Table SEQ Table ARABIC 12 Effect of temperature on high shear homogenization TemperatureTime in minRPMGlobule Size (Z Average)PDIRT1020006488 nm0.589400C1020001763.8 nm0.511500C1020001471 nm0.479600C1020001102 nm0.372700C102000842.1 nm0.329800C102000673.4 nm0.299 Table SEQ Table ARABIC 13 Effect of RPM on high shear homogenization TemperatureTime in minRPMGlobule Size (Z Average)PDI60-700C1010008675.9 nm0.87660-700C102000935.9 nm0.31560-700C103000457.9 nm0.245 Above results indicated that the temperature and time is having profound effect on the droplet size reduction of the oil in the emulsion. During the primary emulsification (mixing of Castor-oil/API in the surfactant solution), coarse emulsion size less than ( 1m) can be achieved by homogenization the emulsion for 10 minutes at 60 to 70C. High pressure homogenization Primary emulsion was subjected to different setting of pressure for number of passes in high pressure homogenizer. The globule size reduction data is presented in the table below, Table SEQ Table ARABIC 14 Effect of different pressure setting on globule size reduction Pass NumberHigh pressure homogenizer pressureC54C55C561000 Bar1250 Bar1500 BarGlobule Size (nm)PDIGlobule Size (nm)PDIGlobule Size (nm)PDI1754.90.145684.90.134628.40.1652689.30.156609.30.156551.80.1873613.70.145523.70.134465.20.1664557.10.157472.10.107427.10.1385478.40.125403.40.102358.40.1336424.50.147335.50.116290.50.1477379.20.148289.20.117244.20.1488328.40.178228.40.147183.40.1789265.20.189175.20.158130.20.18910234.60.156139.60.12594.60.15611232.20.153112.20.11667.20.14712231.90.156111.90.11766.90.14813234.90.158104.90.14759.90.17814245.90.25795.90.15850.90.189 Above results indicate that the desired droplet size can be attained after 10 to 13 passes on high pressure homogenizer at a pressure of about 1250 . Further reduction in the droplet size is not significant. Hence on the bases of the above results it is concluded to run the secondary homogenization in the recirculation loop at least for 10 passes to achieve the desired droplet size. Table SEQ Table ARABIC 15 Effect of Temperature and pressure on microemulsion globule size Trial NumberC57C58C55Pressure1250 Bar1250 Bar1250 BarTemp. range25-350C45-550C60-700CNo. of passGlobule Size (nm)PDIGlobule Size (nm)PDIGlobule Size (nm)PDI1984.70.364864.90.268684.90.1342908.40.311790.30.313609.30.1563821.80.269705.50.292523.70.1344769.10.213655.90.262472.10.1075699.40.203587.50.248403.40.1026630.70.231520.30.262335.50.1167583.20.233475.10.251289.20.1178521.90.293415.60.271228.40.1479467.20.315363.80.274175.20.15810430.70.249328.40.241139.60.12511402.50.231302.90.231112.20.11612401.70.233302.20.232111.90.11713400.40.293299.80.253104.90.14714403.70.315300.50.25995.90.158 Above results indicate that the desired droplet size reduction was more efficient with the increase in temperature during high pressure homogenization. Hence on the bases of the above results it is concluded to run the secondary homogenization at about 60-700C to achieve the desired droplet size. Evaluation of formulations Formulation were evaluated for different physicochemical parameter and the summary of results is presented in table below, Table SEQ Table ARABIC 16 Summary of physicochemical parameters Test ParametersFormula AFormula BDescriptionOpaque milky white viscous emulsionOpaque milky white viscous emulsionpH7.016.98Osmolality (mOsmol/kg)298301Viscosity (Cps)209347Specific gravity1.00121.0014Globule size (Z avg nm)112.9114.3PDI0.1750.189Zeta potential (mV)-14.2-12.7Surface Tension (mN/m)28.230.6Assay ()100.199.6In vitro Drug Release (Time in Hrs) Drug Release0000.56.53.7115.48.9232.519.8352.636.8468.949.7579.461.7688.975.7899.876.89100.176.8 Based on the initial evaluation, it was observed that formulations with Hydroxyethylcellulose (MX), as a polymer was equivalent to formulations with Carbomer 974P except the in vitro drug release. Thus, formulations with Carbomer 974P were selected for the further stability studies. Thermodynamic stability ConditionInitialHeating-Cooling CycleFreeze thaw cycle study Cycle 1Cycle 2Cycle 1Cycle 2DescriptionOpaque milky white viscous emulsionOpaque milky white viscous emulsionOpaque milky white viscous emulsionOpaque milky white viscous emulsionOpaque milky white viscous emulsionpH7.016.997.0177.01Osmolality (mOsmol/kg)298300299299301Globule size (Z avg nm)112.9113.1114.2112.6111.9PDI0.1750.1810.1830.1790.181Viscosity (Cps)209202198204199Assay ()100.1100.398.4100.398.4Total Impurities ()0.890.870.910.870.91 Based on the above data, it was observed that microemulsions are thermodynamically stable systems as there was no significant change in physico-chemical parameters. Discussion Description Description of ophthalmic emulsion was observed as Opaque milky white viscous emulsion. Milky appearance to the emulsion system, supposed to be due to presence of oil phase dispersed in water along with the surfactant. Opaqueness was observed due to the presence of viscosity modifier. Description of the ophthalmic emulsion was found to be unchanged during the stability studies. pH The excipients used in the formulation decide the pH of the final preparation. Change in pH may change zeta potential of formulation which in turn can affect the stability of preparation. So pH is also responsible for stability of microemulsion. All the formulations pH was adjusted to about 6.9 to 7.2 value. No pH shift was observed during the stability studies. Osmolality The osmolality of the prepared ophthalmic microemulsion was in the range of 290 to 320 mOsml/kg. No osmolality changes were observed during the stability studies. Specific gravity The specific gravity of the prepared ophthalmic microemulsion was in the range of 1.0000 to 1.0020. Specific gravity is not a stability indicating parameter, so no monitored during the stability. Viscosity Viscosity of microemulsion systems depends on viscosity modifier agent used and somewhat on the pH. The viscosity of the prepared ophthalmic microemulsion was in the range of 195 to 250 cps. Surface tension The surface tension values obtained for the microemulsion were in the range of 28.2 36.7 mN/m which is lower than the physiological value of the lachrymal fluid surface tension which ranges from 40 to 50 mN/m9. This result was expected because of the large amounts of surfactants used in the preparation of microemulsion. Administration of eye drops with lower surface tension than that of the lachrymal fluid resulted in destabilization of the tear film 10, 11. Film which can guarantee a good spreading effect on the cornea and mixing with the precorneal film constituents, thus possibly improving the contact between the drug and the corneal epithelium12.The low surface tension obtained for the developed microemulsion, thus, destabilized the tear and enhance the drug solubilization from the microemulsion. Zeta potential The droplet size of microemulsion is important criteria for evaluation and it should be less than 100 nm. Microemulsions with low droplet size are usually more stable compared with microemulsions with larger droplet size because larger droplets are more susceptible to aggregation or creaming. Zeta potential is related to surface charge of microemulsion droplet. The zeta potential governs the stability of Microemulsion. It is important to measure its value for stability samples. The high value of zeta potential indicates electrostatic repulsion between two droplets. DLVO theory states that electric double layer repulsion will stabilize microemulsion where electrolyte concentration in the continuous phase is less than a certain value. The theory states that system remains stable due to de-flocculation of microemulsion particles and for identical system zeta potential charge should be between ranges of -10 to -30 mV13. Globule size Globule size of oil droplet in microemulsion was determined by photon correlation spectroscopy that analyzes the fluctuations in light scattering due to Brownian motion of the particles using a Zetasizer (Nano-ZS, Malvern Instruments, UK). The formulation (0.1 mL) was dispersed in 50 mL of water in a volumetric flask, mixed thoroughly with vigorous shaking, and light scattering was monitored at 25C at a 90angle. Whereas zeta potential was measured using a disposable zeta cuvette. For each sample, the mean diameter/zeta potential standard deviation of three determinations was calculated applying multimodal analysis. The globule size of the formulations was observed in the range of 100 to 120 nm and found to be similar during the stability studies. Drug Content and Related substances The drug content test was performed for the both the drugs. The amount of the Cyclosporine content in the selected formulations A and D was in the range of 98-101 of the added amount. The assay of Cyclosporine in ophthalmic microemulsion formulation revealed presence of the drug in the range of 98-99 in all formulations under the study. The results of assay revealed suitability of the system for high entrapment of drug in the internal phase. Morphological characterization Microscopic images of primary emulsion formed by the high shear homogenizer are given below. From the images, it was observed that uniform primary emulsion was formed by the high shear homogenizer. Figure SEQ Figure ARABIC 3 Microscopic images of primary emulsion and TEM images of Cyclosporine ophthalmic microemulsion TEM image of prepared microemulsion system of cyclosporine (Formula A) is shown below. It may be confirmed from the figure that uniform droplet size of the prepared system was observed. Cyclosporine drug particles incorporated in oil droplet which was surrounded by water molecule. It confirms the formation of oil in water (o/w) microemulsion system. In vitro drug release Effect of Viscosity of emulsion In vitro drug release for microemulsion with Carbomer and Hydroxyethylcellulose (MX), polymers is represented as graphical in below figure, Based on this data, it is clear that, higher viscosity of the formulation retard the drug release, which can be correlated to the drug availability from the ophthalmic emulsion to the eye after instillation. Figure SEQ Figure ARABIC 4 Graphical representation of in vitro drug release Cyclosporine ophthalmic emulsion ACKNOWLEDGEMENT The authors are grateful to the authorities of Department of Pharmacy, Faculty of Allied Health Sciences, Mahatma Jyoti Rao Phoole University, Achrol, Jaipur, India for the facilities. CONFLICT OF INTEREST The authors declare no conflict of interest. REFERENCES M. Gibaldi and D. Perrier. Pharmacokinetics. New York Marcel Dekker, 1982 S. Tamilvanan, R.N. Gursoy, S. Benita, Emulsion-based delivery systems for enhanced drug absorption, Pharm. Tech. 131 (2002) 156161. G. Marti-Mestres, F. Nielloud, Emulsions in health care applications, J. Dispersion Sci. Technol. 23 (2002) 419439. H. Sasaki, K. Yamamura, K. Nishida, J. Nakamura, M. Ichikawa, Delivery of drugs to the eye by topical application, Prog. Retin. Eye Res. 15 (1996) 583620. Capek, I., Radical polymerization of polar unsaturated monomers in direct microemulsion systems. Adv Colloid Interface Sci, 1999. 80(2) p. 85-149. Gelbart, W.M. and A. BenShaul, The new science of complex fluids. Journal of Physical Chemistry, 1996. 100(31) p. 13169-13189 Holmberg, K., Handbook of applied surface and colloid chemistry. 2002, Chichester New York Wiley. Fialho SL, da Silva-Cunha A. New vehicle based on a microemulsion for topical ocular administration of dexamethasone. Clin Experiment Ophthalmol 200432626-32 Miller D. Measurement of the surface tension of tears. Arch Ophthalmol 196982368-71. Lin SP, Brenner H. Marangoni convection in a tear film. J Colloid Interface Sci 19828559-65. EGGnR5g95 xIZ
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