smedds

Smedds

1. Self Micro Emulsifying Drug Delivery Systems

2. Table of Contents 2

3. INTRODUCTION Self micro emulsifying drug delivery (SMEDDS) 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. The concept was introduced by Haur and Schulman in 1940’s, who generated a single phase solution by titrating a milky emulsion with hexanol. Schulman and co-workers in 1959 subsequently coined the term microemulsion. Micro emulsion have been successively used to improve the solubility, chemical stability and oral bioavalability of poorly soluble drugs ( class II and IV as per BCS classification)[1] 3

4. Fig1: Pictorial representation of SMEDDS[2] 4

5. Composition 5

6. Drug: The ideal log p value of the drug should be ( log p>2) No extensive first pass metabolism. Drug should be soluble in lipids, solvents and co-solvents . 2) Oil : Oils solubilizes lipophilic drugs Facilitates intestinal lymphatic uptake Modified/ hydrolyzed vegetable oils- good emulsification systems[3]. Oils 6

7. Medium chain triglycerides (MCT) having carbon atoms between 6 and 12 are directly transported by portal blood to the systemic circulation. Long chain triglycerides (LCT) having carbon atoms greater than 12 are transported via intestinal lymphatics MCT are widely used due to: Higher solvent capacity No oxidation Examples: LCT: soya bean oil, corn oil, peanut oil, MCT: miglycol 812,captex 355, labrafac 7

8. Surfactants : Surfactants assist instantaneous formation of o/w droplets Surfactants used to stabilize microemulsion system Medium chain length alcohols (C3–C8) are commonly employed as co-surfactants Non ionic with high HLB value High HLB and hydrophilicity leads to excellent spreading properties Example: Polysorbate 20 (tween 20), Polysorbate 80 (tween 80), Sorbitan monooleate (Span 80),Polyoxy-35-castor oil( Cremophor RH40)[7]. 8

9. Co-surfactant: Ensures flexibility of the interfacial layer i.e , Co-surfactants it reduces the interfacial tension to a negative value. are added to further lower the interfacial tension between the oil and water phase, to fluidize the hydrocarbon region of interfacial film, and to influence the film curvature. Examples: short chained alcohol ( ethanol, propanol, butanol) Glycol (propylene glycols)[4]. 9

10. Mechanism of Self Emulsification The free energy formed in SMEDDS can be given by the following equation Where, ∆G – free energy accompanying the process (apart from the free energy of mixing), N – Total number of droplets π r 2 –area of the droplets σ – Energy at the interface [1] Lower the interfacial energy. 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 ∆G=∑N π r 2 σ 10

11. Formulation design 11

12. SCREENING : Solubility Studies: These are mainly useful for the selection of the most suitable excipients that can be used in the preparation of SMEDDS and helps in the prediction of drug precipitation in vivo . Screening of Surfactants and Cosurfactants for their self emulsification ability. The emulsification ability of surfactants can be known by mixing the equal proportions of selected oil and surfactant which is followed by homogenization[5]. 12

13. Construction of Pseudoternary Phase Diagram: These are the diagrams which represent change in phase behavior of the system according to the change in composition. Ternary phase diagram is used to study the phase behavior of three components. In SMEDDS, this represents the system with three components like oil, water, and surfactant. But in case of addition of fourth component, the ternary diagram can be called pseudoternary phase diagram and corner can be the mixture of two components like surfactant and cosurfactant. Ternary diagram contains three corners that correspond to the 100% of the particular component[7]. 13

14. Pseudoternary diagrams are constructed by keeping the ratio of any two of the four components as constant and this ratio along with the remaining two components generally forms three corners of the phase diagram. This fixed (mixture) ratio is generally formed by the combination of surfactant and cosurfactant and sometimes it may be the mixture of oil and surfactant. This is mixed with the required volume of the third phase like oil or cosurfactant ,then the other component which is usually water is added in incremental amounts and for every addition of fourth component, the solution should be tested for the clarity, flowability, time for self-emulsification, and dispersibility. The total percent concentration of all components in each mixture should be 100%/

15. The three corners of the typical ternary diagram represent three components, that is, A, B, and C. The arrow towards BA indicates increase in proportion of A from 0% concentration (at point B) to 100% concentration (at point A), the arrow towards AC indicates the increase in proportion of C from 0% concentration (at point A) to 100% concentration (at point C) Similarly the arrow towards CB indicates the increase in proportion of B from 0% concentration (at point C) to 100% concentration (at point B).

16. Composition at point “O” can be known by the following. ( i ) Draw a line that is parallel to CB from point O towards AB. The point where this line intersects with AB indicates the percent composition of A at point O (X). (ii) Then, percent composition of B at point O can be known by drawing a line that is parallel to AC towards BC. The point where this line intersects with BC indicates the percent composition of B at point O (Y). (iii) Similarly, the percent composition of C at point O can be known by drawing a line that is parallel to AB towards AC (Z)

17. WINSOR PHASE BEHAVIOUR DIAGRAMS: WINSOR-1 :- With two phases, the lower (o/w) microemulsion phase in equilibrium with excess oil. WINSOR-2 :- With two phases, upper (w/o) microemulsion phase in equilibrium with excess water. WINSOR-3 :- With three phases, middle microemulsion phase (o/w plus w/o, called bio-continuous) in equilibrium with upper excess oil and lower excess water. WINSOR-4 :- In single phase, with oil, water, and surfactant homogenously mixed

18. Grade A: Rapidly forming microemulsion 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 Grade D: Dull, greyish white emulsion having slightly oily appearance that is slow to emulsify

19. PREPARATION OF SMEDDS: The preparation involves the addition of drug to the mixture of oil, surfactant, and co-surfactant and then it should be subjected to vortexing. In some cases, drug is dissolved in any one of the excipients and the remaining excipients are added to the drug solution . The solution should be properly mixed and tested for the signs of turbidity. The solution should be heated for the formation of clear solution[8]. 21

20. Characterization of Smedds: 22

21. CHARACTERIZATION OF SMEDDS: Visual Evaluation: The assessment of self emulsification is possible by visual evaluation. After dilution of SMEDDS with water, the opaque and milky white appearance indicates the formation of macroemulsion whereas the clear, isotropic, transparent solution indicates the formation of microemulsion . 23

22. Droplet Size Analysis: The droplet size is mainly dependent on the nature and concentration of surfactant. Microemulsion formed upon dilution with water produces droplets of very narrow size and size distribution for effective drug release, in vivo absorption, and also stability Time for Emulsification: The time needed for selfemulsification for different formulations can be assessed generally using dissolution apparatus USP type II in which the formulation is added dropwise to the basket containing water and observing the formation of clear solution under agitation provided by paddle at 50 rpm[9] 24

23. Cloud Point Determination: Cloud point is generally determined by gradually increasing the temperature of water bath in which the formulation is placed and measured spectrophotometrically. Zeta Potential : Zeta potential is generally measured by zeta potential analyzer, Value of zeta potential indicates the stability of emulsion. Higher zeta potential indicates the good stability of formulation[9]. 25

24. Viscosity Measurements: Viscosity of diluted SMEDDS formulation that is microemulsion is generally determined by rheometers like Brookfield cone and plate rheometer fitted with cone spindle or rotating spindle Brookfield viscometer . Dilution Studies : It is done in various diluents like double distilled water, simulated gastric fluid (SGF), and simulated intestinal fluid (SIF) Refractive index: The constant refractive index indicates the thermodynamic stability of the formulation . Usually the refractive index measurements are carried out using refractometers[10] . 26

25. APPLICATIONS 27

26. APPLICATIONS 28

27. MARKETED PREPARATIONS Brand Drug Dosage form Indications Neoral ® Cyclosporine Soft gelatin capsule immunosuppressant Norvir ® Ritonavir Soft gelatin capsule HIV antiviral Lipire ® Fenofibrate Hard gelatin capsule Lowering of TG level Convule ® Valproic acid Soft gelatin capsule Antiepileptic Table: 1 Applications of SMEDDS reported in literature[12] 29

28. ADVANTAGES 30

29. LIMITATIONS 31

30. RECENT ADVANCES Supersaturable SMEDDS: Telmisartan (TMS) Self micro-emulsifying mouth dissolving film (SMMDF) : SMMDF of vitamin D3 for infants Formulations of lecithin linker for SE delivery of nutraceuticals Sponges carrying SMEDDS : alginate based composite as gastroretentive carrier for curcumin loaded SMEDDS Herbal SMEDDS: Ginkgo biloba extract loaded SMEDDS[11]   Self-double emulsifying drug delivery system: pidotimod-SDEDDS  Positively charged SEDDS[2] 32

31. CONCLUSION For poorly water soluble drugs, a self-emulsifying drug delivery method in solid dosage form increases solubility/dissolution, absorption, and bioavailability. This approach is best for lipophilic medicines because the subsequent emulsification allows for quicker disintegration and absorption. SMEDDS outperforms competing colloidal vehicles in terms of cost savings, ease of industrial manufacturing, and improved stability and patient compliance. 33

32. REFERENCES 1) Dokania S, Joshi AK. Self-microemulsifying drug delivery system (SMEDDS)–challenges and road ahead. Drug delivery. 2015 Aug 18;22(6):675-90. 2) https://www.researchgate.net/figure/Method-for-the-preparation-of-SMEDDS_fig1_348407856 3) Deshmukh AS. Recent advances in self emulsifying drug delivery system. International Journal of Pharmaceutical Sciences and Nanotechnology. 2015 Feb 28;8(1):1-5glycol. 4) Savale S, Chalikwar S. Self Micro Emulsifying Drug Delivery System (SMEDDS): A Review. Asian Journal of Biomaterial Research. 2017;3(2):12-7. 34

33. 5) Akula S, Gurram AK, Devireddy SR. Self-microemulsifying drug delivery systems: an attractive strategy for enhanced therapeutic profile. International scholarly research notices. 2014;2014. 6) Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced drug delivery reviews. 1997 Jan 15;23(1-3):3-25. 7)https://www.jyoungpharm.org/sites/default/files/JYoungPharm_10_2_132_1.pdf 35

34. 8) Sharma V, Singh J, Gill B, Harikumar SL. SMEDDS: A novel approach for lipophilic drugs. International Journal of Pharmaceutical Sciences and Research. 2012 Aug 1;3(8):2441. 9) Sharma V, Singh J, Gill B, Harikumar SL. SMEDDS: A novel approach for lipophilic drugs. International Journal of Pharmaceutical Sciences and Research. 2012 Aug 1;3(8):2441. 10) Jaiswal P, Aggarwal G. Bioavailability enhancdement of poorly soluble drugs by smedds: a review. Journal of drug delivery and therapeutics. 2013 Jan 14;3(1). 11) Zhang L, Zhang L, Zhang M, Pang Y, Li Z, Zhao A, Feng J. Self-emulsifying drug delivery system and the applications in herbal drugs. Drug delivery. 2015 May 19;22(4):475-86. 36

35. 12)Jaiswal P, Aggarwal G. Bioavailability enhancdement of poorly soluble drugs by smedds: a review. Journal of drug delivery and therapeutics. 2013 Jan 14;3(1). 37

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