self emulsifyin drug delivery system

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SELF EMULSIFYING DRUG DELIVERY SYSTEM (SEDD):

SELF EMULSIFYING DRUG DELIVERY SYSTEM (SEDD) K.V.RAMANA REDDY Asso.Professor Naresh Babu B.Pharmacy Final year

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INTRODUCTION Numerous potent lipophilic drugs exhibit low oral bio-availability due to their poor aqueous solubility properties. Isotropic mixtures of natural synthetic oils Improving oral bioavailability of poorly water soluble and lipophilic drugs. SEDDS can exist in either liquid or solid states. SEDDS are usually, however, limited to liquid dosage forms, because many excipients used in SEDDS are not solids at room temperature

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Fine oil droplet easily pass from stomach Promote wide distribution of drug in GI Tract Minimizes irritation of drug in gut wall High physical stable incidence Partitioning of drug b/w oil and water more by imparting large interfacial area Reproducibility in plasma concentration profiles Resultant liquid is clear SPECIAL UNIQUE FEATURES

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Potential Advantages of these systems include 1. Enhanced oral bioavailability enabling reduction in dose, 2. More consistent temporal profiles of drug absorption, 3. Selective targeting of drug(s) toward specific absorption window in GIT, 4. Protection of drug(s) from the hostile environment in gut. 5. Protective of sensitive drug substances 6. Liquid or solid dosage form 7.High drug pay load

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Mechanism of self emulsification self‐emulsification occurs when the entropy change that favors dispersion is greater than the energy required to increase the surface area of the dispersion. The free energy of the conventional emulsion is a direct function of the energy required to create a new surface between the oil and water phases.

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NEED OF SEDD Enhanced oral bioavailability enabling reduction in dose, 2. More consistent temporal profiles of drug absorption, 3. Selective targeting of drug(s) toward specific absorption window in GIT 4. Protection of drug(s) from the hostile environment in gut. 5. Protective of sensitive drug substances 6. Liquid or solid dosage forms

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GENERAL FORMULATION APPROACH Oils Surfactants Co-solvents • The solubility of drug in the formulation as such and upon dispersion (for SEDDS), • The rate of digestion (for formulations susceptible to digestion) and possibly • The solubilization capacity of the digested formulation.

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Release pattern profile of drug into lumen

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A.Oils Both long- and medium-chain triglyceride (MCT) oils with different degrees of saturation have been used for the design of self-dispersing formulations. Unmodified edible oils provide the most `natural' basis for lipid vehicles, but hydrophobic drugs and their relative difficulty in efficient self-emulsification markedly reduce their use in SEDDS

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B. Surfactants: Non-ionic surfactants with a relatively high hydrophilic ±lipophilic balance (HLB) were advocated for the design of self-dispersing systems, where the various liquid or solid ethoxylated poly glycolyzedglycerides and polyoxyethylene 20 oleate (Tween 80) are the most frequently used excipients. Emulsifiers derived from natural sources are expected to be safer than synthetic ones and are recommended for SDLF (self dispersed lipid formulation) use40,58,60,61, despite their limited ability to self-emulsify. Non-ionic surfactants are known to be less toxic compared to ionic surface-active agents, but they may cause moderate reversible changes in intestinal wallpermeability6, 62.. A large quantity of surfactant may irritate the GI tract.

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Polysorbate 20 (Tween 20 Polysorbate 80 (Tween 80) Sorbitan monooleate (Span 80) Polyoxy-35-castor oil(Cremophor RH40) Polyoxy-40- hydrogenated castor oil (Cremophor RH40) Polyoxyethylated glycerides (Labrafil M 2125 Cs) Polyoxyethlated oleic glycerides (Labrafil M1944

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C. Co-solvents Relatively high surfactant concentrations (usually more than 30% w/w) are needed in order to produce an effective self-emulsifying system. Organic solvents, suitable for oral administration (ethanol, propylene glycol(PG), polyethylene glycol (PEG), etc.) may help to dissolve large amounts of either the hydrophilic surfactant or the drug in the lipid base.

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Ideal properties of excipients Be safe, inert and available at a purity level Highly stable Be capable of solubilizing the drug dose in a volume not exceeding that of an oral capsule It possess surface active properties to enable self-emulsification complete dissolution of the drug dose Reliably and reproducibly in the oral bioavailability of the drug relative to a conventional formulation

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ADVANTAGES OF SMEDDS OVER EMULSION It also overcomes the drawback of the layering of emulsions after sitting for a long time. SMEDDS can be easily stored since it belongs to a thermodynamics stable system. Micro emulsions formed by the SMEDDS exhibit good thermodynamics stability and optical transparency. The major difference between the above micro emulsions and common emulsions lies in the particle size of droplets. SMEDDS offer numerous delivery options like filled hard gelatin capsules or soft gelatin capsules or can be formulated in to tablets whereas emulsions can only be given as an oral solutions.

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DISADVANTAGES OF SMEDDS One of the obstacles for the development of SMEDDS and other lipid-based formulations is the lack of good predicative in vitro models for assessment of the formulations. Traditional dissolution methods do not work, because these formulations potentially are dependent on digestion prior to release of the drug. This in vitro model needs further development and validation before its strength can be evaluated. Further development will be based on in vitro - in vivo correlations and therefore different prototype lipid based formulations needs to be developed and tested in vivo in a suitable animal model. The drawbacks of this system include chemical instabilities of drugs and high surfactant concentrations in formulations (approximately 30-60%) which irritate GIT.

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Role of excipient used in solid self emulsification system Self‐emulsifying solid dosage form mainly contains oil, surfactant, co surfactant, filler etc. A wide range of oils has been studied either as model system or as potential vehicles for the dosage forms, with many of the oils under study being medium chain fatty acid ester or a medium/long chain saturated, partially unsaturated or unsaturated hydrocarbon, in liquid, semisolid or solid form at room temperature. Very polar or non‐polar oils tend to form poor emulsions. Miglyol 812 and 840 both have intermediate polarity which shows favorable emulsification properties with Tween85.

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Mechanism absorption of lipid base formulation

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FACTORS AFFECTING SMEDDS Nature and dose of the drug Polarity of the lipophilic phase Drugs which are administered at very high dose are not suitable for SMEDDS unless they exhibit extremely good solubility in at least one of the components of SMEDDS, preferably lipophilic phase. The polarity of the lipid phase is one of the factors that govern the drug release from the micro emulsions. The polarity of the droplet is governed by the HLB, the chain length and degree of unsaturation of the fatty acid, the molecular weight of micronized for their propensity to inhibit crystallization and, thereby, generate and maintain the supersaturated state for prolonged time periods

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Technique of solid SEDDS development i) Solid carriers ii) Spray Drying iii) Melt extrusion iv) Dry Emulsion These solid carriers have property to absorb liquid/semisolid formulation as self emulsifying system (SES). In this technique first the prepared formulation containing oil, surfactant, drug, solid carrier etc, is sprayed into a drying chamber through a nozzle. This formulation technique depends on the property of the plastic mass material which can be easily extruded and speronised with pressure. It is mainly O/W emulsion, which is then converted into solid form by spray drying/solid carrier/ freeze drying

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Role of excipient used in solid self emulsification system Self ‐ emulsifying solid dosage form mainly contains oil, surfactant, cosurfactant, filler etc. A wide range of oils has been studied either as model system or as potential vehicles for the dosage forms, with many of the oils under study being medium chain fatty acid ester or a medium/long chain saturated, partially unsaturated or unsaturated hydrocarbon, in liquid, semisolid or solid form at room temperature. In SEDDS we can use different types of oil for examples mono, di triglycerides of fatty acids, fatty alcohols, vegetable oils, mineral oils, refined animal oils etc 19. Nature of oil is very important in the formation of SEDDS. Chemicals structure of the oil components and interactions of these components with the various enzymes, surfactants and proteins associated with digestion and absorption process, for example, fatty acid chain length is important factor for chylomicron formation.

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Biopharmaceutical aspects 1.Al terations (reduction) in gastric transit 2.Increase in effective luminal drug solubility 3.Stimulation of intestinal lymphatic transport 4. Changes in the biochemical barrier function of the GI tract 5.Changes in the physical barrier function of the GI tract 6.Effect of oils on the absorption

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Developments of solid self emulsifying delivery system Solidification techniques for transforming liquid/ semisolid SEDDS to S ‐ SEDDS include 1. Capsule filling with liquid and semisolid self emulsifying formulations 2. Self emulsifying capsules 3. Self emulsifying sustained/controlled released tablets 4. Self emulsifying sustained/controlled released pellets 5.solid dispersions 6.Self-emulsifying suppositories

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Characterization of SEDDSs 1.Visual assessment This may provide important information about the self emulsifying and micro emulsifying property of the mixture and about the resulting dispersion. 2.Turbidity measurement This is to identify efficient self emulsification by establishing whether the dispersion reaches equilibrium rapidly and in a reproducible time. 3.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.. 4.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. 5.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 formulations.

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EVALUATION 1. Thermodynamic stability studies 2 . Dispersibility test Grade A : Rapidly forming (within 1 min) Nano emulsion, having a clear or bluish appearance. Grade B : Rapidly forming, slightly less clear emulsion, having a bluish white appearance. Grade C : Fine milky emulsion that formed within 2 min. Grade D : Dull, grayish white emulsion having slightly oily appearance that is slow to emulsify (longer than 2 min). Grade E : Formulation, exhibiting either poor or minimal emulsification with large oil globules present on the surface .

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3. Turbid metric Evaluation 4. Viscosity Determination 5. Droplet Size Analysis Particle Size Measurements 6.Refractive Index and Percent Transmittance 7. Electro conductivity Study 8. InVitro Diffusion Study 9. Drug content 12.Visual assessment 11. Determination of emulsification time 10. Zeta potential measurement

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LIMITATIONS Although SEDDs after several advantages over conventional in stabilities of drugs due to high surfactant concentration morover, volatile cosolvents in the conventional emulsifying formulations are known to migrate in to the cells of soft(or)hard gelatin capsules The lack of high quality. n vitro models for evaluation of SEDDs formulations.

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DRWBACK OF SEDDS One of the obstacles for the development of self emulsifying drug delivery systems (SEDDS) and other lipid-based formulations is the lack of good predicative in vitro models for assessment of the formulations. Traditional dissolution methods do not work, because these formulations potentially are dependent on digestion prior to release of the drug. To mimic this, an in vitro model simulating the digestive processes of the duodenum has been developed. This in vitro model needs further development and validation before its strength can be evaluated. Further development will be based on ivitro - in vivo correlations and therefore different prototype lipid based formulations needs to be developed and tested in vivo in a suitable animal model. Future studies will address the development of the in vitro model. n

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REFERENCES 1 . Stegemanna S, Leveillerb F. When poor solubility becomes an issue: from early stage to proof of concept, European Journal Pharmaceutical Science, 31, 2007, 249-261. 2. Murdandea SB, Gumkowskia MJ, Development of a self-emulsifying formulation that reduces the food effect for torcetrapib, International Journal of Phamacy, 351, 2008, 15-22. 3. Grovea M, Mullertzb A, Bioavailability of seocalcitol II: development and characterisation of self-microemulsifying drug delivery systems (SMEDDS) for oral administration containing medium and long chain triglycerides, European Journal Pharmaceutical Science, 28, 2006, 233-42. 4. Tang J, Self-Emulsifying Drug Delivery Systems: strategy for improving oral delivery of poorly soluble drugs, Current Drug Therapy, 2, 2007, 85-93. 5. Lipinski C. Poor aqueous solubility-an industry wide problem in drug discovery, American Pharmacy Review, 5, 2002, 82 – 85.

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CONCLUSION Self ‐ emulsifying drug delivery systems are a promising approach for the formulation of drug compounds with poor aqueous solubility. The oral delivery of hydrophobic drugs can be made possible by SEDDSs, which have been shown to substantially improve oral bioavailability. With future development of this technology, SEDDSs will continue to enable novel applications in drug delivery and solve problems associated with the delivery of poorly soluble drugs.

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I WISH ALL THE BEST FOR VIEWERS -----------------------------------To be continued

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