self micro emulsifying drug delivery system
- 1. S E L F M I C R O - E M U L S I F Y I N G D R U G D E L I V E R Y S Y S T E M S M E D D S AHMED TAHA M.PHARM 1ST SEM DEPT. PHARMACEUTICS AL AMEEN COLLEGE OF PHARMACY SUBMITTED TO : DR ASHA MA’AM
- 2. INTRODUCTION 2 1. SMEDDS are used to solve low bioavailability issues of poorly soluble & highly permeable compounds. Hydrophobic drugs can be dissolved in these systems, enabling them to be administered as a unit dosage form for per-oral administration. 2. SMEDDS consists of a mixture of drugs, oils, surfactants and/or other additives. 3. Gentle mixing of these ingredients in aqueous media generates micro-emulsions with a droplet size in a range of 10-100 nm 4. SMEDDS has been shown to improve absorption of drugs by rapid self-micro emulsification in the stomach, with the micro-emulsion droplets subsequently dispersing in the gastrointestinal tract to reach sites of absorption .
- 3. SELF-MICRO-EMULSIFYING DRUG DELIVERY SYSTEM (SMEDDS) PRESENTATION TITLE 3 • Definition- “SMEDDS are defined as isotropic mixtures of natural or synthetic oils, solid and liquid surfactants”. • or • alternatively, one or more hydrophilic solvents and co-solvents/surfactants that have a unique ability of forming fine oil-in-water (o/w) micro emulsions upon mild agitation followed by dilution in aqueous media, such as GI fluids.
- 4. SEDDS typically produce opaque emulsions with a droplet size between 100 and 300 nm. SMEDDS form transparent micro emulsions with a droplet size of less than 150 nm. the concentration of oil in SMEDDS is less than 20 % as compared to 40- 80% in SEDDS. 4 PRESENTATION TITLE
- 5. AIM OF SMEDDS Most of the new drug candidates in development today are sparingly soluble and associated with poor bioavailability The main purpose is to prepare SMEDDS for “oral bioavailability enhancement of a poorly water-soluble drug”. 5 PRESENTATION TITLE
- 6. TYPES OF SELF MICROEMULSION 1. O/W Micro emulsion 2. W/O Micro emulsion 6 PRESENTATION TITLE
- 8. ADVANTAGES OF SMEDDS 1.Improvement in oral bioavailability 2.Ease of manufacture and scale-up 3.Reduction in inter-subject and intra-subject variability and food effects 4.overcomes the drawback of the layering of emulsions after sitting for a long time and easily stored since it belongs to a thermodynamics stable system. 5.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. 8 PRESENTATION TITLE
- 9. DIS-ADVANTAGES OF SMEDDS 1. Traditional dissolution methods do not work, because these formulations potentially are dependent on digestion prior to release of the drug. 2. 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. 3. The drawbacks of this system include chemical instabilities of drugs and high surfactant concentrations in formulations (approximately 30-60%) which irritate GIT. 4. Moreover, volatile co solvents in the conventional self-micro emulsifying formulations are known to migrate into the shells of soft / hard gelatin capsules, resulting in the precipitation of the lipophilic drugs. 5. The precipitation tendency of the drug on dilution may be higher due to the dilution effect of the hydrophilic solvent. 9 PRESENTATION TITLE
- 10. CHALLENGES IN SMEDDS : 1 0 PRESENTATION TITLE
- 11. APPLICATIONS OF SMEDDS RELEVANT TO BCS CLASSIFICATION: 11 PRESENTATION TITLE
- 12. COMPOSITION OF SMEDDS 1. Oils 2. Surfactants 3. Cosolvents 4. Cosurfactants 1 2 PRESENTATION TITLE
- 13. • Oils can solubilize the required dose of the lipophilic drug and facilitate self-emulsification and also they can increase the fraction of lipophilic drug transported via the intestinal lymphatic system, thereby increasing absorption from the GI tract depending on the molecular nature of the triglyceride • Both long and medium chain triglyceride (LCT and MCT) oils with different degrees of saturation have been used for the design of self- emulsifying formulations. • Novel semisynthetic MCT, which can be defined as amphiphilic compounds with surfactant properties, are progressively and effectively replacing the regular MCT oils in the SMEDDS MCT are more soluble and have a higher mobility in the lipid/water interfaces than LCT associated with a more rapid hydrolysis of MCT. • . 1 3 Oils:
- 14. • In general, when using LCT, a higher concentration of cremophor RH40 is required to form microemulsions compared with MCT. • Edible oils are not frequently selected due to their poor ability to dissolve large amounts of lipophilic drugs. • Modified or hydrolyzed vegetable oils have been widely used since these excipients form good emulsification systems with a large number of surfactants approved for oral administration and exhibit better drug solubility properties . They offer formulative and physiological advantages and their degradation products resemble the natural end products of intestinal digestion. 1 4 PRESENTATION TITLE
- 15. SURFACTANTS • Surfactants form the interfacial film and lower the interfacial tension to a small value which facilitates dispersion process. • HLB value and concentration of surfactant is essential to be considered while selecting a surfactant. • For attaining high emulsifying performance, the emulsifier involved in the formulation of SMEDDS should have high HLB greater than 12 which assists in formation of small o/w droplets and rapid spreading of formulation in aqueous media. • Generally, non-ionic surfactants with HLB 4 to 12 are suggested for design of self-dispersing systems as these are less toxic than ionic surfactants 1 5 PRESENTATION TITLE
- 16. cosolvents 16 Organic solvents such as ethanol, propylene glycol (PG) and polyethylene glycol (PEG) are suitable for oral delivery and they enable the dissolution of large quantities of either the hydrophilic surfactant or the drug in the lipid base. solvents can even act as co surfactants in microemulsion systems. Alternately alcohols and other volatile cosolvents have the disadvantage of evaporating into the shells of the soft gelatin or hard sealed gelatin capsules in conventional SMEDDS leading to drug precipitation.
- 17. CO-SURFACTANTS : • Co-surfactants ensures flexibility of the interfacial layer, i.e. it reduces the interfacial tension to a negative value. • Co-surfactants form a flexible interfacial film in order to acquire different curvatures required to form microemulsion over a wide range of composition. • Medium chain length alcohols (C3–C8) are commonly employed as co-surfactants 1 7 PRESENTATION TITLE
- 18. Oil Phase • Isopropyl Myristate • Oleic acid • Olive oil • Mineral oil • Medium chain triglyceride • Soyabean oil • Captex 355 • Isopropyl Palmitate • Sunflower oil • Safflower oil Surfactant • Tween 80 • Tween 40 • Span 40 • Labrafil M1944CS • Polyoxyethylene-35- ricinoleate • Brij 58 • CremophorEL • Lecithin Co-surfactant • Propylene glycol • Ethylene glycol • Ethanol • 1-butanol • Isopropyl alcohol • PEG 600 • Glycerol • PEG 400 Examples 18
- 19. 1.Phase Titration Method 2.Phase inversion Method • 1. Phase Titration Method dilution of an oil-surfactant mixture with water.(w/o) dilution of a water-surfactant mixture with oil.(o/w) mixing all components at once. In some systems, the order of ingredient addition may determine whether a microemulsion forms. • 2.Phase inversion method Phase Inversion Temperature (PIT), i.e., the temperature range in which an o/w microemulsion inverts to a w/o type or vice versa. 1 9 PRESENTATION TITLE METHOD OF PREPARATION
- 21. 6. FORMULATION DESIGN • Formulation of SMEDDS involves the following steps. 1.Screening of excipients. 2.Construction of pseudoternary phase diagram. 3.Preparation of SMEDDS. 4.Characterization of SMEDDS. 2 1 PRESENTATION TITLE
- 25. Mechanism of Self-Emulsification • The free energy of the emulsion can be described by the following equation: • ΔG = ∑ NΠr2σ. • ΔG is the free energy, N is the number of droplets, r is the radius of droplets, and σ is the interfacial energy. From this equation, it is evident that the lower the interfacial energy the lower the free energy. Self-emulsification occurs when the energy involvement in the dispersion is greater than the energy required for the formation of droplets . The free energy of conventional emulsion is very high as high energy is required to form new surface between two immiscible phases like oil and water. Due to high free energy, the emulsion may not be stable and the two phases tend to separate. 2 5 PRESENTATION TITLE
- 26. EVALUATION TEST 1. Thermodynamic Stability Studies 2. Dispersibility test 3. Turbidimetric Evaluation 4. Viscosity Determination 5. Droplet Size Analysis and Particle Size Measurements 6. Refractive Index and Percent Transmittance 7. Electro Conductivity Study 8. In vitro Diffusion Study 9. Drug Content 10. In vivo permeability studies 2 6 PRESENTATION TITLE
- 27. THERMODYNAMIC STABILITY STUDIES • Heating cooling cycle : • Six cycles between refrigerator temperature 4⁰C and 45⁰C with storage at each temperature of not less than 48 h is studied. •Those formulations, which are stable at these temperatures, are subjected to centrifugation test. 2 7 PRESENTATION TITLE
- 28. CENTRIFUGATION •Passed formulations are centrifuged at room temperature at 3500 rpm for 30 min. •Those formulations that does not show any phase separation are taken for the freeze thaw stress test 2 8 PRESENTATION TITLE
- 29. FREEZE THAW CYCLE • Freeze was employed to evaluate the stability of formulation. • Thermodynamic stability was evaluated at difference temp. To check the effect of temp. the formulation was subjected to freeze thaw cycle(-20ºC) for 2-3 days. • Those formulations passed this test showed good stability with no phase separation, creaming, or cracking. 2 9 PRESENTATION TITLE
- 30. DISPERSIBILITY TEST • The efficiency of self-emulsification of oral nano or micro emulsion is evaluated by using a standard USP • XXII dissolution apparatus for dispersibility test. Solution Tested: 1ml Medium: 500 ml water Temperature: 37 ± 1 ⁰C. Paddle speed : 50 rpm 3 0 PRESENTATION TITLE
- 31. • 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. • Grade A and Grade B formulation will remain as nano-emulsion when dispersed in GIT. While formulation falling in Grade C could be recommended for SMEDDS formulation. 3 1 PRESENTATION TITLE
- 32. TURBIDIMETRIC EVALUATION Nepheloturbidimetric evaluation is done to monitor the growth of emulsification. Fixed quantity of Self emulsifying system is added to fixed quantity of suitable medium (0.1N hydrochloric acid) under continuous stirring (50 rpm) on magnetic hot plate at appropriate temperature, and the increase in turbidity is measured, by using a turbidimeter. However, since the time required for complete emulsification is too short, it is not possible to monitor the rate of change of turbidity (rate of emulsification) 3 2 PRESENTATION TITLE
- 33. VISCOSITY DETERMINATION The SMEDDS system is generally administered in soft gelatin or hard gelatin capsules. So, it should be easily pourable into capsules and such systems should not be too thick. The rheological properties of the micro emulsion are evaluated by Brookfield viscometer. The viscosities determination conform whether the system is w/o or o/w. If the system has low viscosity then it is o/w type of the system If the system has high viscosity then it is w/o type of the system 3 3 PRESENTATION TITLE
- 34. DROPLET SIZE ANALYSIS • The droplet size of the emulsions is determined by photon correlation spectroscopy (which analyses the fluctuations in light scattering due to Brownian motion of the particles) using a Zetasizer able to measure sizes between 10 and 5000 nm 3 4 PRESENTATION TITLE
- 35. REFRACTIVE INDEX AND PERCENT TRANSMITTANCE • Refractive index and percent transmittance prove the transparency of formulation. • The refractive index of the system is measured by refractometer by putting a drop of solution on slide • and comparing it with water (1.333). • The percent transmittance of the system is measured at particular wavelength using UV spectrophotometer by using distilled water as blank. • If refractive index of system is similar to the refractive index of water (1.333) and formulation have percent transmittance > 99 percent, then formulation have transparent nature 3 5 PRESENTATION TITLE
- 36. ELECTRO-CONDUCTIVITY STUDY The SMEDD system contains ionic or non-ionic surfactant, oil, and water. This test is performed for measurement of the electro conductive nature of system The electro conductivity of resultant system is measured by electro conductometer. In conventional SEDDSs, the charge on an oil droplet is negative due to presence of free fatty acids 3 6 PRESENTATION TITLE
- 37. IN VITRO DIFFUSION STUDY • In vitro diffusion studies are carried out to study the drug release behavior of formulation from liquid crystalline phase around the droplet using dialysis technique. 3 7 PRESENTATION TITLE DRUG CONTENT Drug from pre-weighed SMEDDS is extracted by dissolving in suitable solvent. Drug content in the solvent extract was analyzed by suitable analytical method against the standard solvent solution of drug.
- 39. THANK YOU MIRJAM NILSSON MIRJAM@CONTOSO.COM | WWW.CONTOSO.COM