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Microemulsion and Self Emulsification System


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Microemulsion and Self Emulsification System

  1. 1. SEMINAR ON MICROEMUSION & SELF EMUSIFICATION SYSTEM• Guided by: • Prepared by: – Mrs. Vaishali thakkar – Bhavesh Maktarpara – M.Pharm. 1st sem Pharmaceutics Anand Pharmacy College, ANAND 1
  2. 2. Microemulsion• Microemulsions are thermodynamically stable dispersions of oil and water stabilized by a surfactant and, in many cases, also a cosurfactant.• Microemulsions can have characteristic properties such as ultralow interfacial tension, large interfacial area and capacity to solubilize both aqueous and oil-soluble compounds. Anand Pharmacy College, ANAND 2
  3. 3. “Microemulsions are dispersions ofnanometer-sized droplets of an immiscibleliquid within another liquid. Droplet formation isfacilitated by the addition of surfactants andoften also co surfactants.” Anand Pharmacy College, ANAND 3
  4. 4. Theories of Microemulsion Formation**• Historically, three approaches have been used to explain microemulsion formation and stability. They are as follows-1. Interfacial or mixed film theories.2. Solubilization theories.3. Thermodynamic treatments.• The free energy of microemulsion formation can be considered to depend on the extent to which surfactant lowers the surface tension of the oil water interface and change in entropy of the system such that, Gf = γ a - T S• Where, – Gf = free energy of formation – A = change in interfacial area of microemulsion – S = change in entropy of the system – T = temperature – γ = surface tension of oil water interphase• It should be noted that when a microemulsion is formed the change in A is very large due to the large number of very small droplets formed.• In order for a microemulsion to be formed (transient) negative value of was required, it is recognized that while value of is positive at all times, it is very small and it is offset by the entropic component. Anand Pharmacy College, ANAND 4
  5. 5. • The dominant favorable entropic contribution is very large dispersion entropy arising from the mixing of one phase in the other in the form of large number of small droplets. • However there are also expected to be favorable entropic contributions arising from other dynamic processes such as surfactant diffusion in the interfacial layer and monomer- micelle surfactant exchange. • Thus a negative free energy of formation is achieved when large reductions in surface tension are accompanied by significant favorable entropic change. • In such cases, microemulsion is spontaneous and the resulting dispersion is thermodynamically stable.1. Schulman J.H, Stoeckenius, W., Prince, L.M, J. Phys. Chem., 63, 1677-1680. (1959).Mechanism of formation and structure o f microemulsions by electron Microscopy .2. Prince L.M, J. Colloid Interface Sci., 23,165-173 (1967). A theory of aqueous emulsionsI.Negative interfacial tension at the oil/water interface Anand Pharmacy College, ANAND 5
  6. 6. Types of microemulsion systems* • According to Winsor, there are four types of microemulsion phases exists in equilibria, these phases are referred as Winsor phases • They are, Winsor I: With two phases, the lower (o/w) microemulsion phases in equilibrium with the upper excess oil. Winsor II: With two phases, the upper (w/o) microemulsion phase microemulsion phases in equilibrium with lower excess water. Winsor III: With three phases, middle microemulsion phase (o/w plus w/o, called bi continous) in equilibrium with upper excess oil and lower excess water. Winsor IV: In single phase, with oil, water and surfactant homogenously mixed.*Aboofazeli R, LawrenceM.J, Int. J. Pharm., 93,161-175 (1993). Investigations into the formation andcharacterization of phospholipid microemulsions. I. Pseudo-ternary phase diagrams of systems containingwater-lecithin-alcohol-isopropyl myristate.* Hasse A, Keipert, S, Eur. J. Pharm. Biopharm., 430, 179-183 (1997). Development and characterization of Anand Pharmacy College, ANAND 6microemulsions for ocular application.
  7. 7. • Advantages Of Microemulsion Over Other Dosage Forms – Increase the rate of absorption – Eliminates variability in absorption – Helps solublize lipophilic drug – Provides a aqueous dosage form for water insoluble drugs – Increases bioavailability – Various routes like tropical, oral and intravenous can be used to deliver the product – Rapid and efficient penetration of the drug moiety – Helpful in taste masking – Provides protection from hydrolysis and oxidation as drug in oil phase in O/W microemulsion is not exposed to attack by water and air. – Liquid dosage form increases patient compliance. – Less amount of energy requirement. Anand Pharmacy College, ANAND 7
  8. 8. – Aesthetically appealing products can be formulated as trans- parent o/w or w/o dispersions called microemulsions.– These versatile systems are currently of great technological and scientific interest to the researchers because of their potential to incorporate a wide range of drug molecules (hydrophilic and hydrophobic) due to the presence of both lipophilic and hydrophilic domains.– These adaptable delivery systems provide protection against oxidation, enzymatic hydrolysis and improve the solubilization of lipophilic drugs and hence enhance their bioavailability. In addition to oral and intravenous delivery, they are amenable for sustained and targeted delivery through ophthalmic, dental, pulmonary, vaginal and topical routes.– Microemulsions are experiencing a very active development as reflected by the numerous publications and patents being granted on these systems. Anand Pharmacy College, ANAND 8
  9. 9. Component of Microemulsion System• A large number of oils and surfactant are available but their use in the microemulsion formulation is restricted due to their toxicity, irritation potential and unclear mechanism of action.• Oils and surfactant which will be used for the formulation of microemulsion should be biocompatible, non-toxic, clinically acceptable, and use emulsifiers in an appropriate concentration range that will result in mild and non-aggressive microemulsion.• The emphasis is, excipients should be generally regarded as safe (GRAS)[ Anand Pharmacy College, ANAND 9
  10. 10. Main three components1. Oil phase2. Surfactant3. Aqueous Component• If a cosurfactant is used, it may sometimes be represented at a fixed ratio to surfactant as a single component, and treated as a single "pseudo-component".• The relative amounts of these three components can be represented in a ternary phase diagram.• Gibbs phase diagrams can be used to show the influence of changes in the volume fractions of the different phases on the phase behavior of the system. Anand Pharmacy College, ANAND 10
  11. 11. Oil Component• The oil component influences curvature by its ability to penetrate and swell the tail group region of the surfactant monolayer.• As compare to long chain alkanes, short chain oil penetrate the tail group region to a greater extent and resulting in increased negative curvature (and reduced effective HLB).• Following are the different oil are mainly used for the formulation of microemulsion:1. Saturated fatty acid-lauric acid, myristic acid,capric acid2. Unsaturated fatty acid-oleic acid, linoleic acid,linolenic acid3. Fatty acid ester-ethyl or methyl esters of lauric, myristic and oleic acid.• The main criterion for the selection of oil is that the drug should have high solubility in it.• This will minimize the volume of the formulation to deliver the therapeutic dose of the drug in an encapsulated form. Anand Pharmacy College, ANAND 11
  12. 12. Surfactants• The role of surfactant in the formulation of microemulsion is to lower the interfacial tension which will ultimately facilitates dispersion process during the preparation of microemulsion and provide a flexible around the droplets.• The surfactant should have appropriate lipophilic character to provide the correct curvature at the interfacial region.• Generally, low HLB surfactants are suitable for w/o microemulsion, whereas high HLB (>12) are suitable for o/w microemulsion.• Following are the different surfactants are mainly used for microemulsion- – Polysorbate (Tween 80 and Tween 20), Lauromacrogol 300, Lecithins, Decyl polyglucoside (Labrafil M 1944 LS), Polyglyceryl-6-dioleate (Plurol Oleique), Dioctyl sodium sulfosuccinate (Aersol OT), PEG-8 caprylic/capril glyceride (Labrasol). Anand Pharmacy College, ANAND 12
  13. 13. Co surfactants• Cosurfactants are mainly used in microemulsion formulation for following reasons:• They allow the interfacial film sufficient flexible to take up different curvatures required to form microemulsion over a wide range of composition.1. Short to medium chain length alcohols (C3-C8) reduce the interfacial tension and increase the fluidity of the interface.2. Surfactant having HLB greater than 20 often require the presence of cosurfactant to reduce their effective HLB to a value within the range required for microemulsion formulation.• Following are the different cosurfactant mainly used for microemulsion: – sorbitan monoleate, sorbitan monosterate, propylene glycol, propylene glycol monocaprylate (Capryol 90), 2-(2-ethoxyethoxy)ethanol (Transcutol) and ethanol. Anand Pharmacy College, ANAND 13
  14. 14. Preparation of Microemulsion• Following are the different methods are used for the preparation of microemulsion*:1. Phase titration method2. Phase inversion method Anand Pharmacy College, ANAND 14
  15. 15. Phase titration method• Microemulsions are prepared by the spontaneous emulsification method (phase titration method) and can be portrayed with the help of phase diagram.• As quaternary phase diagram (four component system) is time consuming and difficult to interpret, pseudo ternary phase diagram is constructed to find out the different zones including microemulsion zone, in which each corner of the diagram represents 100% of the particular components.• Pseudo-ternary phase diagrams of oil, water, and co- surfactant/surfactants mixtures are constructed at fixed cosurfactant/surfactant weight ratios.• Phase diagrams are obtained by mixing of the ingredients, which shall be pre-weighed into glass vials and titrated with water and stirred well at room temperature. Formation of monophasic/ biphasic system is confirmed by visual inspection. Anand Pharmacy College, ANAND 15
  16. 16. Anand Pharmacy College, ANAND 16
  17. 17. • In case turbidity appears followed by a phase separation, the samples shall be considered as biphasic.• In case monophasic, clear and transparent mixtures are visualized after stirring; the samples shall be marked as points in the phase diagram. – The area covered by these points is considered as the microemulsion region of existence. Anand Pharmacy College, ANAND 17
  18. 18. Phase inversion method• Phase inversion of microemulsion is carried out upon addition of excess of the dispersed phase or in response to temperature.• During phase inversion drastic physical changes occur including changes in particle size that can ultimately affect drug release both in vitro and in vivo.• For non-ionic surfactants, this can be achieved by changing the temperature of the system, – forcing a transition from an o/w microemulsion at low temperature – to - – a w/o microemulsion at higher temperatures (transitional phase inversion). Anand Pharmacy College, ANAND 18
  19. 19. • During cooling, the system crosses a point zero spontaneous curvature and minimal surface tension, promoting the formation of finely dispersed oil droplets.• Apart from temperature, salt concentration or pH value may also be considered.• A transition in the radius of curvature can be obtained by changing the water volume fraction.• Initially water droplets are formed in a continuous oil phase by successively adding water into oil. Increasing the water volume fraction changes the spontaneous curvature of the surfactant from initially stabilizing a w/o microemulsion to an o/w microemulsion at the inversion locus. Anand Pharmacy College, ANAND 19
  20. 20. • Many examples of microemulsion based formulations are now on the market ; – Among them, the performances of microemulsions are well demonstrated in the reformulation of Cyclosporin A by Novartis into a microemulsion based formulation marketed under the trade mark Neoral®• this has increased the bioavailability nearly by a factor 2. Anand Pharmacy College, ANAND 20
  21. 21. Characterization Of Microemulsion1. The droplet size,2. viscosity,3. density,4. turbidity,5. refractive index,6. phase separation and7. pH measurements shall be performed to characterize the microemulsion. Anand Pharmacy College, ANAND 21
  22. 22. The droplet size• The droplet size distribution of microemulsion vesicles can be determined by either light scattering technique or electron microscopy.• This technique has been advocated as the best method for predicting microemulsion stability. – Dynamic light-scattering measurements. • The DLS measurements are taken at 90° in a dynamic light- scattering spectrophotometer which uses a neon laser of wavelength 632 nm. The data processing is done in the built-in computer with the instrument. Anand Pharmacy College, ANAND 22
  23. 23. Phase analysis and viscosity measurement • Polydispersity – Studied using Abbe refractometer. • Phase analysis – To determine the type if microemulsion that has formed the phase system (o/w or w/o) of the microemulsions is determined by measuring the electrical conductivity using a conductometer. • · Viscosity measurement – The viscosity of microemulsions of several compositions can be measured at different shear rates at different temperatures using Brookfield type rotary viscometer. – The sample room of the instrument must be maintained at 37 ± 0.2°C by a themobath, and the samples for the measurement are to be immersed in it before testing. Anand Pharmacy College, ANAND 23
  24. 24. In Vitro Drug Permeation Studies• Determination of permeability coefficient and flux – Excised human cadaver skin from the abdomen can be obtained from dead who have undergone postmortem not more than 5 days ago in the hospital. The skin is stored at 4C and the epidermis separated. – The skin is first immersed in purified water at 60C for 2 min and the epidermis then peeled off. – Dried skin samples can be kept at -20C for later use. – Alternatively the full thickness dorsal skin of male hairless mice may be used. – The skin shall be excised, washed with normal saline and used. Anand Pharmacy College, ANAND 24
  25. 25. – The passive permeability of lipophilic drug through the skin is investigated using Franz diffusion cells with known effective diffusional area.– The hydrated skin samples are used. The receiver compartment may contain a complexing agent like cyclodextrin in the receiver phase, which shall increase the solubility and allows the maintenance of sink conditions in the experiments.– Samples are withdrawn at regular interval and analyzed for amount of drug released. Anand Pharmacy College, ANAND 25
  26. 26. In Vivo Studies• Bioavailability studies: Skin bioavailability of topical applied microemulsion on rats – Male Sprague–Dawley rats (400–500 g), need to be anesthetized (15 mg/kg pentobarbital sodium i.p.) and placed on their back. – The hair on abdominal skin shall be trimmed off and then bathed gently with distilled water. – Anesthesia should be maintained with 0.1-ml pentobarbital (15 mg/ml) along the experiment. – Microemulsions must be applied on the skin surface (1.8 cm2) and glued to the skin by a silicon rubber. – After 10, 30 and 60 min of in vivo study, the rats shall be killed by aspiration of ethyl ether. – The drug exposed skin areas shall be swabbed three to four times with three layers of gauze pads, then bathed for 30 s with running water, wiped carefully, tape-stripped (X10 strips) and harvested from the animals. Anand Pharmacy College, ANAND 26
  27. 27. • Determination of residual drug remaining in the skin on tropical administration. – The skin in the above permeation studies can be used to determine the amount of drug in the skin. The skin cleaned with gauze soaked in 0.05% solution of sodium lauryl sulfate and shall bathed with distilled water. – The permeation area shall be cut and weighed and drug content can be determined in the clear solution obtained after extracting with a suitable solvent and centrifuging. Anand Pharmacy College, ANAND 27
  28. 28. • Pharmacological Studies – Therapeutic effectiveness can be evaluated for the specific pharmacological action that the drug purports to show as per stated guidelines.• Estimation Of Skin Irritancy – As the formulation is intended for dermal application skin irritancy should be tested. – The dorsal area of the trunk is shaved with clippers 24 hours before the experiment. – The skin shall be scarred with a lancet. 0.5 ml of product is applied and then covered with gauze and a polyethylene film and fixed with hypoallergenic adhesive bandage. – The test be removed after 24 hours and the exposed skin is graded for formation of edema and erythema. – Scoring is repeated a 72 hours later. – Based on the scoring the formulation shall be graded as • ‘non-irritant’, • ‘irritant’ and • ‘highly irritant’. Anand Pharmacy College, ANAND 28
  29. 29. • Stability Studies – The physical stability of the microemulsion must be determined under different storage conditions (4, 25 and 40 °C) during 12 months. – Depending on different regulatory agency requirement it’ll vary according to them. – Fresh preparations as well as those that have been kept under various stress conditions for extended period of time is subjected to droplet size distribution analysis. – Effect of surfactant and their concentration on size of droplet is also be studied. Anand Pharmacy College, ANAND 29
  30. 30. Application of microemulsion in delivery of drug• Oral delivery – Microemulsions have the potential to enhance the solubilization of poorly soluble drugs (particularly BCS class II or class IV) and overcome the dissolution related bioavailability problems. – These systems have been protecting the incorporated drugs against oxidation, enzymatic degradation and enhance membrane permeability. – Presently, Sandimmune Neoral(R) (Cyclosporine A), Fortovase(R) (Saquinavir), Norvir(R) (Ritonavir) etc. are the commercially available microemulsion formulations. – Microemulsion formulation can be potentially useful to improve the oral bioavailability of poorly water soluble drugs by enhancing their solubility in gastrointestinal fluid. Anand Pharmacy College, ANAND 30
  31. 31. • Parenteral delivery – The formulation of parenteral dosage form of lipophilic and hydrophilic drugs has proven to be difficult. – O/w microemulsions are beneficial in the parenteral delivery of sparingly soluble drugs where the administration of suspension is not required. – They provide a means of obtaining relatively high concentration of these drugs which usually requires frequent administration. – Other advantages are that they exhibit a higher physical stability in plasma than liposome’s or other vehicles and the internal oil phase is more resistant against drug leaching. – Several sparingly soluble drugs have been formulated into o/w microemulsion for parenteral delivery. Anand Pharmacy College, ANAND 31
  32. 32. • Topical delivery – Topical administration of drugs can have advantages over other methods for several reasons, one of which is the avoidance of hepatic first-pass metabolism of the drug and related toxicity effects. – Another is the direct delivery and targetability of the drug to affected areas of the skin or eyes. – Now a day, there have been a number of studies in the area of drug penetration into the skin. – They are able to incorporate both hydrophilic (5- flurouracil, apomorphine hydrochloride, diphenhydramine hydrochloride, tetracaine hydrochloride, methotrexate) and lipophilic drugs (estradiol, finasteride, ketoprofen, meloxicam, felodipine, triptolide) and enhance their permeation. Anand Pharmacy College, ANAND 32
  33. 33. • Ophthalmic delivery – Low corneal bioavailability and lack of efficiency in the posterior segment of ocular tissue are some of the serious problem of conventional systems. – Recent research has been focused on the development of new and more effective delivery systems. – Microemulsions have emerged as a promising dosage form for ocular use. – Chloramphenicol, an antibiotic used in the treatment of trachoma and keratitis, in the common eye drops hydrolyzes easily. – Fialho et al. studied microemulsion based dexamethasone eye drops which showed better tolerability and higher bioavailability. The formulation showed greater penetration in the eye which allowed the possibility of decreasing dosing frequency and thereby improve patient compliance. Anand Pharmacy College, ANAND 33
  34. 34. • Nasal delivery – Recently, microemulsions are being studied as a delivery system to enhance uptake of drug through nasal mucosa. – In addition with mucoadhesive polymer helps in prolonging residence time on the mucosa. – Lianly et al. investigated the effect of diazepam on the emergency treatment of status epilepticus. – They found that the nasal absorption of diazepam fairly rapid at 2 mg kg-1 dose with maximum drug plasma concentration reached within 2-3 min Anand Pharmacy College, ANAND 34
  35. 35. • Drug targeting – Drug targeting to the different tissues has evolved asthe most desirable goal of drug delivery. – By altering pharmacokinetics and biodistribution of drugs and restricting their action to the targeted tissue increased drug efficacy with concomitant reduction of their toxic effects can be achieved. – Shiokawa et al. reported a novel microemulsion formulation for tumor targeting of lipophilic antitumor antibiotic aclainomycin A (ACM). – They reported that a folate-linked microemulsion is feasible for tumour targeted ACM delivery. – They also reported that folate modification with a sufficiently long PEG chain on emulsions is an effective way of targeting emulsion to tumour cells. Anand Pharmacy College, ANAND 35
  36. 36. Self Emulsification Drug Delivery System Anand Pharmacy College, ANAND 36
  37. 37. • SEDDSs are isotropic mixtures of oils and surfactants, sometimes containing cosolvents, and can be used for the design of formulations in order to improve the oral absorption of highly lipophilic compounds.• SEDDSs emulsify spontaneously to produce fine oil-in-water emulsions when introduced into an aqueous phase under gentle agitation.• SEDDS can be orally administered in soft or hard gelatine capsules and form fine, relatively stable oil-in-water emulsions upon aqueous dilution. Anand Pharmacy College, ANAND 37
  38. 38. • Self-emulsifying formulations spread readily in the gastrointestinal (GI) tract, and the digestive motility of the stomach and the intestine provide the agitation necessary for selfemulsification.• These systems advantageously present the drug in dissolved form and the small droplet size provides a large interfacial area for the drug absorption.• SEDDSs typically produce emulsions with a droplet size between 100–300 nm while self-microemulsifying drug delivery systems (SMEDDSs) form transparent microemulsions with a droplet size of less than 50 nm. Anand Pharmacy College, ANAND 38
  39. 39. • Composition of SEDDSs – The self-emulsifying process is depends on: • The nature of the oil–surfactant pair • The surfactant concentration • The temperature at which self-emulsification occurs. Anand Pharmacy College, ANAND 39
  40. 40. • Oils – Oils can solubilize the lipophilic drug in a specific amount. It is the most important excipient because it can facilitate self-emulsification and increase the fraction of lipophilic drug transported via the intestinal lymphatic system, thereby increasing absorption from the GI tract. – Long-chain triglyceride and medium-chain triglyceride oils – Modified or hydrolyzed vegetable oils have contributed widely to the success of SEDDSs owing to their formulation and physiological advantages Anand Pharmacy College, ANAND 40
  41. 41. • Surfactant – Nonionic surfactants with high hydrophilic– lipophilic balance (HLB) values are used in formulation of SEDDSs (e.g., Tween, Labrasol, Labrafac CM 10, Cremophore, etc.). – The usual surfactant strength ranges between 30– 60% w/w of the formulation in order to form a stable SEDDS. Anand Pharmacy College, ANAND 41
  42. 42. • Cosolvents – Cosolvents like diehylene glycol monoethyle ether (transcutol), propylene glycol, polyethylene glycol, polyoxyethylene, propylene carbonate, tetrahydrofurfuryl alcohol polyethylene glycol ether (Glycofurol), etc., may help to dissolve large amounts of hydrophilic surfactants or the hydrophobic drug in the lipid base. – These solvents sometimes play the role of the cosurfactant in the microemulsion systems. Anand Pharmacy College, ANAND 42
  43. 43. Formulation of SEDDSs• The following should be considered in the formulation of a SEDDS: – The solubility of the drug in different oil, surfactants and cosolvents. – The selection of oil, surfactant and cosolvent based on the solubility of the drug and the preparation of the phase diagram. – The preparation of SEDDS formulation by dissolving the drug in a mix of oil, surfactant and cosolvent. Anand Pharmacy College, ANAND 43
  44. 44. • The addition of a drug to a SEDDS is critical because the drug interferes with the self- emulsification process to a certain extent, which leads to a change in the optimal oil–surfactant ratio.• So, the design of an optimal SEDDS requires preformulation-solubility and phase-diagram studies. In the case of prolonged SEDDS, formulation is made by adding the polymer or gelling agent Anand Pharmacy College, ANAND 44
  45. 45. Mechanism of self-emulsification• According to Reiss, self-emulsification occurs when the entropy change that favors dispersion is greater than the energy required to increase the surface area of the dispersion. Where, DG is the free energy associated with the process N is the number of droplets R is radius of droplet S is interfacial tension Anand Pharmacy College, ANAND 45
  46. 46. Characterization of SEDDSs• The primary means of self-emulsification assessment is visual evaluation. The efficiency of self-emulsification could be estimated by determining the rate of emulsification, droplet- size distribution and turbidity measurements.• Visual assessment. This may provide important information about the self-emulsifying and microemulsifying property of the mixture and about the resulting dispersion.• Turbidity Measurement. This is to identify efficient self- emulsification by establishing whether the dispersion reaches equilibrium rapidly and in a reproducible time. Anand Pharmacy College, ANAND 46
  47. 47. • Droplet Size. – This is a crucial factor in self-emulsification performance because it determines the rate and extent of drug release as well as the stability of the emulsion. – Photon correlation spectroscopy, microscopic techniques or a Coulter Nano sizer are mainly used for the determination of the emulsion droplet size. – The reduction of the droplet size to values below 50 μm leads to the formation of SMEDDSs, which are stable, isotropic and clear o/w dispersions.• Zeta potential measurement. – This is used to identify the charge of the droplets. In conventional SEDDSs, the charge on an oil droplet is negative due to presence of free fatty acids.• Determination of emulsification time. – Self-emulsification time, dispersibility, appearance and flowability was observed and scored according to techniques described in H. Shen et al. used for the grading of Anand Pharmacy College, ANAND formulations. 47
  48. 48. References• Microemulsions- Potential Carrier for Improved Drug Delivery INTERNATIONALE PHARMACEUTICA SCIENCIA April-June 2011 Vol. 1 Issue 2 ISSN 2231-5896 ©2011 IPS, Sajal Kumar Jha1*, Sanjay Dey1, Roopa Karki2• N.H. Shah et al., "Self-emulsifying drug delivery systems (SEDDS) with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs," Int. J. Pharm. 106, 15–23 (1994).• J.R. Crison and G.L. Amidon, "Method and formulation for increasing the bioavailability of poorly water-soluble drugs," US Patent No. 5,993,858, issued November 30, 1999.• P.P. Constantinides, "Lipid microemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects," Pharm. Res. 12, 1561–72 (1995).• N. Gursoy et al., "Excipient effects on in vitro cytotoxicity of a novel paclitaxel selfemulsifying drug delivery system," J. Pharm. Sci. 92, 2420–2427 (2003). Anand Pharmacy College, ANAND 48