Self emulsifying drug delivery system by rohan satwara


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Self Emulsifying Drug Delivery System:

Self Emulsifying Drug Delivery System Presented by : Rohan Satwara M.pharm Sem II Babaria Institute of Pharmacy, Varnama.

: Content ::

: Content : Marketed preparation Conclusion Bibliography Questions Terms Introduction LCFS Ternary phase diagram Formulation aspects Mechanism Advantage and disadvantages Evaluation criteria Factors affecting SEDDS Biopharmaceutical aspects DFD in SEDDS 2 SEDDS

Terms :

Terms SEDDS 3 Emulsion Micro emulsion SEDDS, SMEDDS, S-SEDDS BCS class II (Poor solubility) HLB Surfactant Co-surfactant and co-solvent

Introduction :

Introduction SEDDS or self-emulsifying oil formulations (SEOF) are defined as Isotropic mixtures of natural or synthetic oils, solid or liquid surfactants or, alternatively, one or more hydrophilic solvents and co-solvents/ surfactants. Self-emulsification is a term used to describe emulsification which occurs with little or no input of energy . The process may be spontaneous or may require low levels of shear – but will contrast with Conventional Emulsification which requires high shear. These systems form fine oil-in-water (o/w) emulsions or micro emulsions (SMEDDS)upon Mild agitation followed by dilution in aqueous media, such as gastrointestinal (GI) fluids. SEDDS 4

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The drug, therefore, remains in solution in the gut, avoiding the dissolution step that frequently limits the absorption rate of hydrophobic drugs from the crystalline state. SEDDS 5

Microemulsions, SEDDS and SMEDDS:

Microemulsions, SEDDS and SMEDDS In the pharmaceutical world a distinction has been made between SEDDS and SMEDDS, on the basis that the latter are visibly transparent . The basic difference between SEDDS also called as self emulsifying oil formulation (SEOF) and SMEDDS is, SEDDS typically produce opaque emulsions with a droplet size between 100 and 300 nm while SMEDDS form transparent micro emulsions with a droplet size of less than 50 nm also the concentration of oil in SMEDDS is less than 20 % as compared to 40-80% in SEDDS. The visual clarity of an emulsion of 50nm particles may offer a Marketing advantage, particularly if the emulsification takes place ex vivo. SEDDS 6

Lipid Formulation Classification System:

Lipid Formulation Classification System LFCS was introduced as a working model in 2000 and an extra ‘type’ of formulation was added in 2006. This classification helps to better understand the fate of different lipid formulation IN VIVO , it also helps To use a systematic & rational formulation approach to avoid “trials and error” iterations To provide framework to guide regulatory agencies. The main purpose is to facilitate the identification of the most appropriate formulations for specific drugs, i.e. with reference to their physicochemical properties. SEDDS 7

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SEDDS 8 Increasing hydrophilic content → OIL SEEDS SMEDDS SMEDDS OIL FREE TYPE I TYPE II TYPE IIIA TYPE IIIB TYPE IV Typical composition (%) Triglycerides or mixed glycerides 100 40–80 40–80 <20 - Water-insoluble surfactants (HLB<12) - 20–60 - - 0–20 Water-soluble surfactants (HLB>12) - - 20–40 20–50 30-80 Hydrophilic co-solvents - - 0–40 20–50 0–50 Particle size of dispersion (nm) Coarse 100–250 100–250 50–100 <50 Significance of aqueous dilution Limited importance Solvent capacity unaffected Some loss of solvent capacity Significant phase changes sand potential loss of solvent capacity Significant phase changes and potential loss of solvent capacity Significance of digestibility Crucial requirement Not crucial but likely to occur Not crucial but may be inhibited Not required Not required

Ternary phase diagram:

Ternary phase diagram Pseudo ternary phase diagram is used to map the optimal composition range for three key excipients according to the resulting droplet size following self emulsification, stability upon dilution and viscosity. SEDDS 9 A Titration method is employed to construct phase diagram. Mixture of oil with surfactant is prepared at different ratios (e.g. 10:0, 9:1, 8:2, 7:3, 6:4, 5:5, 4:6, 3:7, 2:8, 1:9, 0:10) into different vials. A small amount of water in 5 % (w /w) increments is added into the vials. Following each water addition the mixture in vials is centrifuged for 2 to 3 minute and is incubated at 25  C or 48 hrs with gentle shaking.

Construction of phase diagram :

Construction of phase diagram SEDDS 10 The resulting mixture is evaluated by visual and microscopy observation. For phase diagram the micro emulsion is the region of clear and isotropic solution. Coarse emulsion is the region of cloudy dispersion.

Formulation of SEEDS :

Formulation of SEEDS Drug Oils Surfactant Co surfactant Co solvent Consistency builder Polymer SEDDS 11

Drug Mainly BCS classification class II drugs : :

Drug Mainly BCS classification class II drugs : Glibenclamide Griseofulvin Haloperidol Ibuprofen Phenytoin Sodium FOLIC acid SEDDS 12 Nifedipine, Cyclosporin, Digoxin Steroids, Diazepam Artemether Carbamazepine


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 with different degrees of saturation have been used in the design of SEDDSs. EG.mono-di-tri-glycerides DL-alpha-Tocopherol, Fractionated triglyceride of coconut oil(medium-chain triglyceride) Corn oil, Olive oil, Oleic acid, Sesame oil, Hydrogenated soya bean oil, Hydrogenated vegetable oils,Soyabean oil, Peanut oil, Beeswax SEDDS 13

Surfactant :

Surfactant 1: Anionic Surfactants , where the hydrophilic group carries a negative charge such as carboxyl (RCOO-), sulphonate (RSO3 -) or sulphate (ROSO3 -). Examples: Potassium laurate, SLS 2: Cationic surfactants , where the hydrophilic group carries a positive charge. Example: quaternary ammonium halide. 3: Ampholytic surfactants (also called zwitterionic surfactants) Example: sulfobetaines. 4: Nonionic surfactants , where the hydrophilic group carries no charge but derives its water solubility from highly polar groups such as hydroxyl or polyoxyethylene (OCH2CH2O). Examples: Sorbitan esters (Spans), Polysorbate (Tween). Nonionic surfactants with high Hydrophilic Lipophilic Balance (HLB) values are used in formulation of SEDDS (e.g., Tween, Labrasol, Labrafac CM 10, Cremophore, etc.). 30–60% w/w is used of the formulation in order to form a stable SEDDS. Surfactants have a high HLB(>12) and hydrophilicity, which assists the immediate formation of o/w droplets and/or rapid spreading of the formulation in the aqueous media SEDDS 14


Cosolvents/Cosurfactant 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 and can act as co-surfactant in the self emulsifying drug delivery systems SEDDS 15

Other components :

Other components These may be pH adjusters, flavors,and Antioxidant agents . Lipophilic antioxidants(E.g. alpha tocopherol, propyl gallate,ascorbyl palmitate ) may be required to stabilize the oily content of SMEDDS formulation. Consistency builder SEDDS 16

Mechanism :

Mechanism The process by which self-emulsification takes place is not yet well understood. But ,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. 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 and can be described by the equation: ΔG = Σ N π r 2 σ Where, ΔG is the free energy associated with the process (ignoring the free energy of mixing), N is the number of droplets of radius r and σ represents the interfacial energy. In the case of self-emulsifying systems, the free energy required to form the emulsion is either very low and positive or negative (then, the emulsification process occurs spontaneously). Lesser interfacial tension lesser free energystable emulsion SEDDS 17

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SEDDS 18 Potential Mechanism for Absorption Enhancement

Advantages :

Advantages Improvement in oral bioavailability: Dissolution rate dependant Increase in specific surface  more efficient drug transport through absorptive brush border membrane leading to improved bioavailability. E.g. In case of Halofantrine approximately 6-8 fold increase in bioavailability of drug was reported in comparison to tablet formulation. Ease of manufacture and scale-up: SMEDDS require very simple and economical manufacturing facilities like simple mixer with agitator and volumetric liquid filling equipment for large-scale manufacturing. This explains the interest of industry in the SMEDDS. SEDDS 19


Cont.. Reduction in inter-subject and intra-subject variability and food effects: Ability to deliver peptides that are prone to enzymatic hydrolysis in GI. No influence of lipid digestion process as found in other LDDS. Increased drug loading capacity Protection of sensitive drug substances. SEDDS 20

Disadvantage :

Disadvantage The drawbacks of this system include chemical instabilities of drugs and high surfactant concentrations. The large quantity of surfactant in self-emulsifying formulations (30-60%) irritates GIT. Volatile cosolvents in the conventional self-emulsifying formulations are known to migrate into the shells of soft or hard gelatin capsules, resulting in the precipitation of the lipophilic drugs. One of the obstacles for the development of self micro emulsifying drug delivery systems (SMEDDS) and other lipid-based formulations is the lack of good predicative in vitro models for assessment of the formulation. SEDDS 21

Evaluation of SEDDS:

Evaluation of SEDDS STABILITY STUDIES 1.Heating cooling cycle: Six cycles ,(4°C) and (45°C) for 48 hrs. 2. Centrifugation: 21°C and 25°C with storage at ach temperature for not less than 48 h is done at 3500 rpm for 30 min. 3. Freeze thaw cycle DISPERSABILITY TEST The efficiency of self emulsification of oral nano or micro emulsion is assessed using a standard USP XXII dissolution apparatus 2. 1ml of each formulation is added to 500 ml of water at 37 ± 0.5°C. A standard stainless steel dissolution paddle is used at 50 RPM . Grade A: Rapidly forming (within 1 min) nano emulsion having a clear or bluish appearance. Grade B: Rapidly forming slightly less clear having a bluish white appearance. Grade C: Fine milky emulsion that forms within 2 min. Grade D: Dull grayish white emulsion having slightly oily appearance that is slow to emulsify. Grade E: Formulation exhibiting either poor or minimal emulsification with large oil globules present on the surface. Grade A and Grade B formulation will remain as nanoemulsion when dispersed in GIT. While formulation falling in Grade C could be recommend for SMEDDS formulation. SEDDS 22

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TURBIDIMETRIC EVALUTION This is done to identify efficient self emulsification by establishing whether the dispersion reaches equilibrium rapidly and in a reproducible time. Nephelo turbid metric evaluation is done to monitor the growth of emulsification. DROPLET SIZE AND PARTICAL SIZE MEASUREMENT Most crucial for drug release and stability Photon correlation spectroscopy (which analyses the fluctuations in light scattering due to Brownian motion of the particles) which can measure sizes between 10 and 5000 nm. REFRACTIVE INDEX AND PERCENT TRANMISSION Refractive index and percent transmittance proves the transparency of formulation Refractometer is generally used UV visible spectrophotometer is used for % transmittance. SEDDS 23

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ZETA POTENTIAL MEASUREMENT : This is used to identify the charge of the droplets . In conventional SMEDDS, the charge on an oil droplet is negative due to presence of free fatty acids. DRUG CONTENT: Drug content in the solvent extract of pre weighed SEDDS was analyzed by suitable analytical method against the standard solvent solution of drug. IN VITRO DRUG DIFFUSION STUDY : It is done using a Dialysis technique. The dialyzing medium was phosphate buffer pH 6.8. One end of pre-treated cellulose dialysis tubing (7 cm in length) was tied with thread, and then 1 ml of self-emulsifying formulation was placed in it along with 0.5 ml of dialyzing medium. SEDDS 24

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Cont….. The other end of the tubing was also secured with thread and was allowed to rotate freely in 200 ml of dialyzing medium and stirred continuously at 100 rpm with magnetic bead on magnetic plate at 37°C. The % drug diffused is measured. SEDDS 25


FACTORS AFFECTING SMEDDS 1. CONCENTRATION OF DRUG: 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. 2. SOLUBILITY OF DRUG: The ability of SMEDDS to maintain the drug in solubilised form is greatly influenced by the solubility of the drug in oily phase. If the surfactant and co-surfactant contribute to a greater extent for solubilisation then there is risk of precipitation. 3. POLARITY OF LIPID PHASE: The polarity of lipid phase is one of the factors that govern the release of the drug from the micro-emulsion. HLB, chain length, degree of unsaturation of the fatty acid, molecular weight of the hydrophilic portion andconcentration of the emulsifier govern polarity of the droplets. SEDDS 26


DFD in SEDDS SOLID SEDDS Means solid dosage form with SEDDS properties.It is done by incorporating liquid or semisolid SEDDS into powders/ nanoparticles or by different solidification techniques (e.g. adsorptions to solid carriers, spray drying, melt extrusion, nanoparticle technology, and so on. DRY emulsion Dry emulsion formulations are typically prepared from oil/ water (O/W) emulsions containing a solid carrier (lactose, maltodextrin, and so on) in the aqueous phase by rotary evaporation, freeze-drying. 4. SELF EMULSIFYING CAPSULES After administration of capsules containing conventional liquid SE formulations, microemulsion droplets form and subsequently disperse in the GI tract to reach sites of absorption. SELF-EMULSIFYING SUSTAINED/CONTROLLED-RELEASE TABLETS Solidifying agent is used for preparation of tablet such as colloidal silicon dioxide ,polyethylene oxide etc.. Now a days , Elementory osmotic pump is designed for SE drug formulation. SEDDS 27

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Cont… 5. Self-emulsifying sustained/controlled-release pellets 6. Self-emulsifying solid dispersions 7. Self-emulsifying beads,eg porous polystyrene beads containing SE were reported 8. Self-emulsifying sustained-releas microspheres EG.HPMC sand aerosil 200 produced SE SR microspheres of zedoary turmeric oil were reported SEDDS 28


Cont…. 9. Self-emulsifying nanoparticles Eg . 5 FU loaded PLGA/O-CMC(o carboxymethyl co glycolide ) nanoparticles was realized. 10. Self-emulsifying suppositories EG. glycyrrizine suppositories 11. Self-emulsifying implants EG.wafer implants of carmustine using cremophore RH 40 sand labrafil 1944 was reported SEDDS 29

Biopharmaceutical aspects:

Biopharmaceutical aspects Lipids may enhance bioavailability via a number of potential mechanisms, including: Alterations (reduction) in gastric transit, thereby slowing delivery to the absorption site and increasing the time available for dissolution. Increases in effective lumenal drug solubility Stimulation of intestinal lymphatic transport. For highly lipophilic drugs, lipids may enhance the extent of lymphatic transport and increase bioavailability directly or indirectly via a reduction in first-pass metabolism. SEDDS 30

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Cont.. Changes in the biochemical barrier function of the GI tract. It is clear that certain lipids and surfactants may attenuate the activity of intestinal efflux transporters, as indicated by the p glycoprotein efflux pump, and may also reduce the extent of enterocytes-based metabolism. Changes in the physical barrier function of the GI tract. Various combinations of lipids, lipid digestion products sand surfactants have been shown to have permeability enhancing properties SEDDS 31

Marketed products:

Marketed products SEDDS 32

Conclusion :

Conclusion SEEDS substantially improved solubility/dissolution, absorption sand bioavailability of poorly water soluble drugs. As improvement or alternatives of conventional liquid SEEDS such as S-SEDDS is superior in reducing production cost, simplifying industrial manufacture, and improving patient compliance and stability. The efficiency of the SEEDS formulation is cases-specific in most instances; thus, composition of the SEEDS formulation should be determined very carefully. Since a relatively high concentration of surfactants is generally employed in the SEEDS formulation, toxicity of the surfactant being used should be taken into account. SEDDS 33

Bibliography :

Bibliography Kyatanwar A U et al. / Self micro-emulsifying drug delivery system (SMEDDS) : Review Journal of Pharmacy Research 2010, 3(1),75-83 KUMAR A et al./SELF EMULSIFYING DRUG DELIVERY SYSTEM (SEDDS): FUTURE ASPECTS, International Journal of Pharmacy and Pharmaceutical Sciences. Vol 2, Suppl 4, 2010 Pathak Aet al. / Recent advances in self emulsifying drug delivery system - A review, Drug Invention Today 2010,2(2),123-129 Mishra N et al,/ Der Pharmacia Lettre New Strategy for Solubilization of poorly soluble drug- SEDDS 2009, 1 (2) 60-67 BO tang et al,/Development of solid self emulsifying drug delivery system : preparation techniques and dosage forms, Drug discovery today,vol 13,july 2008, 13-14 KAMBLE A V et al/ SELF MICRO EMULSIFYING DRUG DELIVERY SYSTEM,International Journal of Pharma and Bio Sciences V1(2)2010 SEDDS 34

GTU question:

GTU question Write a short note on self emulsifying drug delivery system. SEDDS 35

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