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Abhijit Dave

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Microemulsions

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Abhijit Dave

  1. 1.  Prepared by: ◦ Abhijit Dave ◦ M.Pharm.2nd sem Pharma Tech Guided by: ◦ Mr. Milind ThosarBabaria Institute of pharmacy, Vadodara 4/21/2012 1
  2. 2. Babaria Institute of pharmacy, Vadodara 4/21/2012 2
  3. 3. • Microemulsions are thermodynamically stable dispersions of oil and water stabilized by a surfactant and, in many cases, also a cosurfactant. Diameter - 10-140 nm. Microemulsions can have characteristic properties such as ultralow interfacial tension, large interfacial area and capacity to solubilize both aqueous and oil-soluble compounds. Babaria Institute of pharmacy, Vadodara 4/21/2012 3
  4. 4. “Microemulsions are dispersions ofnanometer-sized droplets of an immiscibleliquid within another liquid. Droplet formationis facilitated by the addition of surfactants andoften also co surfactants.” And they can be known as Moderncolloidal drug delivery system. Babaria Institute of pharmacy, Vadodara 4/21/2012 4
  5. 5.  The Microemulsion concept was introduced as early as 1940s by Hoar and Schulman who generated a clear single-phase solution by titrating a milky emulsion with hexanol. Schulman and co-worker (1959) subsequently coined the term microemulsion The microemulsion definition provided by Danielson and Lindman in 1981 will be used as the point of reference. Babaria Institute of pharmacy, Vadodara 4/21/2012 5
  6. 6.  Transparent emulsion Swollen micelle Micellar solution Solubilized oil Babaria Institute of pharmacy, Vadodara 4/21/2012 6
  7. 7. Macro emulsion Micro emulsion Babaria Institute of pharmacy, Vadodara 4/21/2012 7
  8. 8. Babaria Institute of pharmacy, Vadodara 4/21/2012 8
  9. 9. FEATURES MACRO EMULSION MICRO EMULSIONDEFINITION Emulsions consist of roughly They constantly evolve spherical droplets of one phase between various structures dispersed into the other ranging from droplet like swollen micelles to bi continuous structure.DROPLET 1 – 20 mm. 10 – 100 nm.SIZEAPPEARANCE Most emulsions are opaque (white) Microemulsions are because bulk of their droplets is transparent or translucent greater than wavelength of light and most oils have higher refractive indices than water. Babaria Institute of pharmacy, Vadodara 4/21/2012 9
  10. 10. FEATURES MACRO EMULSION MICRO EMULSIONPHASES Two OneSTABILITY Stable but coalesce finally More thermodynamically stable than macroemulsionsPREPARATION Require intense agitation Generally obtained by for their formation. gentle mixing of ingredients.SURFACTANT 2-3 % Weight 6-8% by weightCONCENTRATION Babaria Institute of pharmacy, Vadodara 4/21/2012 10
  11. 11.  O/W Microemulsion W/O Microemulsion Bi continuous Microemulsion Babaria Institute of pharmacy, Vadodara 4/21/2012 11
  12. 12.  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. Babaria Institute of pharmacy, Vadodara 4/21/2012 12
  13. 13. ◦ 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 reflectedofby the numerous publications Babaria Institute pharmacy, Vadodara 4/21/2012 13
  14. 14.  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. Babaria Institute of pharmacy, Vadodara 4/21/2012 14
  15. 15. 1. 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. Babaria Institute of pharmacy, Vadodara 4/21/2012 15
  16. 16.  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. Babaria Institute of pharmacy, Vadodara 4/21/2012 16
  17. 17.  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). Babaria Institute of pharmacy, Vadodara 4/21/2012 17
  18. 18.  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. Babaria Institute of pharmacy, Vadodara 4/21/2012 18
  19. 19. Babaria Institute of pharmacy, Vadodara 4/21/2012 19
  20. 20.  Packing ratio Property of surfactant Property of oil phase Temperature Chain length Type and nature of cosurfactant Babaria Institute of pharmacy, Vadodara 4/21/2012 20
  21. 21.  Following are the different methods are used for the preparation of microemulsion*:1. Phase titration method2. Phase inversion method Babaria Institute of pharmacy, Vadodara 4/21/2012 21
  22. 22.  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. Babaria Institute of pharmacy, Vadodara 4/21/2012 22
  23. 23. Babaria Institute of pharmacy, Vadodara 4/21/2012 23
  24. 24.  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. Babaria Institute of pharmacy, Vadodara 4/21/2012 24
  25. 25.  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 ofat higher temperatures Babaria Institute pharmacy, Vadodara 4/21/2012 25
  26. 26.  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 Babaria Institute of pharmacy, locus. Vadodara 4/21/2012 26
  27. 27.  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. Babaria Institute of pharmacy, Vadodara 4/21/2012 27
  28. 28. 1. 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. Babaria Institute of pharmacy, Vadodara 4/21/2012 28
  29. 29.  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. Babaria Institute of pharmacy, Vadodara 4/21/2012 29
  30. 30.  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. Babaria Institute of pharmacy, Vadodara 4/21/2012 30
  31. 31.  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 Babaria Institute of pharmacy, Vadodara 4/21/2012 31
  32. 32. ◦ 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. Babaria Institute of pharmacy, Vadodara 4/21/2012 32
  33. 33.  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. Babaria Institute of pharmacy, Vadodara 4/21/2012 33
  34. 34.  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. Babaria Institute of pharmacy, Vadodara 4/21/2012 34
  35. 35.  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‟. Babaria Institute of pharmacy, Vadodara 4/21/2012 35
  36. 36.  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. Babaria Institute of pharmacy, Vadodara 4/21/2012 36
  37. 37. APPLICATIONS Babaria Institute of pharmacy, Vadodara 4/21/2012 37
  38. 38.  Oral drug delivery Ocular drug delivery Pulmonary drug delivery Transdermal drug delivery Parenteral drug delivery For solubilization of drug Nasal delivery Drug targeting In biotechnlogy others Babaria Institute of pharmacy, Vadodara 4/21/2012 38
  39. 39.  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. Babaria Institute of pharmacy, Vadodara 4/21/2012 39
  40. 40.  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. Babaria Institute of pharmacy, Vadodara 4/21/2012 40
  41. 41.  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. Babaria Institute of pharmacy, Vadodara 4/21/2012 41
  42. 42.  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 Babaria Institute of pharmacy, improve patient compliance. Vadodara 4/21/2012 42
  43. 43.  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 Babaria Institute of pharmacy, Vadodara 4/21/2012 43
  44. 44.  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. Babaria Institute of pharmacy, Vadodara 4/21/2012 44
  45. 45.  Microemulsions are optically isotropic and thermodynamically stable liquid solutions of oil, water and amphiphile. Microemulsions are readily distinguished from normal emulsions by their transparency, low viscosity and more fundamentally their thermodynamic stability. Drug delivery through microemulsions is a promising area for continued research with the aim of achieving controlled release with enhanced bioavailability and for drug targeting to various sites in the body. Babaria Institute of pharmacy, Vadodara 4/21/2012 45
  46. 46.  Microemulsions- Potential Carrier for Improved Drug Delivery INTERNATIONALE PHARMACEUTICA SCIENCIA April-June 2011 Vol. 1 Issue 2 http://www.ipharmsciencia.com 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). Babaria Institute of pharmacy, Vadodara 4/21/2012 46
  47. 47. Babaria Institute of pharmacy, Vadodara 4/21/2012 47

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