Self-Micro Emulsifying Drug Delivery Systems (SMEDDS): An Emerging Strategy to Improve Oral Bioavailability of Poorly Soluble Drugs

FIGURE 1

Specific approaches have been used in the formulation process to increase the oral bioavailability of certain medications. Among these, oral lipid-based drug-delivery systems (DDS) have demonstrated enormous promise in enhancing the inconsistent and poor drug absorption of numerous weakly water-soluble medications, particularly when administered after meals.^9,10 Despite having poor absorption characteristics, emulsions are used as drug carriers in pharmaceutical preparations, even though they might probably increase the medicine's oral bioavailability.¹¹ One of the most common methods for improving the stability of APIs that are taken orally is to use lipid-based drug delivery vehicles. The terminology used for lipid-based treatments is hotly contested, according to the literature. The main determinant of micro and nano emulsions (SMEDDS and SNEDDS) is not the initial droplet size.Self-emulsifying oil formulations, or SMEDDS, are isotropic blends of liquid or solid surfactants, natural or synthetic oils, or, alternatively, one or more hydrophilic solvents and co-solvents/surfactants. In recent years, SMEDDS have drawn a lot of attention as potential carriers for the administration of proteins and peptides orally.¹² The kind and quality of the surfactant concentration, the oil/surfactant combination, the oil/surfactant ratio, and the physiological conditions—such as pH and temperature—all affect self-emulsification. SMEDDSs differ from traditional oral drug delivery systems in that the excipients in the formulation are drastically altered by the digestion of enzymes.¹³To tackle this problem, a variety of strategies have been employed, such as structural drug modifications, the addition of auxiliary agents, and the creation of SEDDS nanocarriers, which are a popular term for self-nano- and self-micro emulsifying drug delivery systems (SNEDDS/SMEDDS) in numerous studies and have proven to be an effective technique for oral medications.¹⁴ As seen in Figure 2, SMEDDSs spontaneously generate fine oil-in-water nano-emulsions with droplet sizes of 200 nm or less. This occurs after aqueous dispersion and slight agitation (as in the GI tract).¹⁵

FIGURE 2

MEDDS:

Solid-lipid nanoparticles (SLN), liposomes, lipoplexes, macroemulsion (coarse emulsion), microemulsion, and self-micro emulsifying drug delivery systems (SMEDDS) are the primary components of lipid-based formulations. Lipid-based formulations have received a lot of attention lately, with SMEDDS receiving special attention.¹⁶ The most effective and preferred technique for increasing oral bioavailability is SMEDDS. SMEDDS are a type of emulsion that has received particular attention as a way to improve the oral bioavailability of medications that are poorly soluble.¹⁷ SMEDDS and other lipid-based formulations are emulsions with strong thermodynamic stability and smaller globule sizes.^{18, 19, 20}

Emulsions are often defined as the dispersion of macroscopic droplets of one liquid (usually water, oil, and emulsifier) in another liquid, with a droplet size of 1–10 mm. They are a viscous, semi-transparent to hazy liquid with a strong interfacial layer that is thermodynamically unstable. There are three types of emulsions: water-in-oil (w/o), oil-in-water (o/w), and multiple emulsions.²¹ A dispersion of oil in water, known as an oil-in-water (o/w) emulsion, is particularly useful for medicinal applications. It necessitates that the emulsifying agent be more soluble in the aqueous phase. Water-in-oil (w/o), the opposite emulsion, is stabilised by surfactants that persist in the oil phase. Conversely, ternary systems of the w/o/w or o/w/o type are known as double emulsions, in which the scattered droplets contain smaller droplets of a separate phase.

Although SMEDDS's microemulsion droplets have 100% entrapment capacity.²² and shield the drug from gastrointestinal degradation, they may be able to deliver medications that are poorly soluble in water. Significantly more drug is absorbed when the drug substance is transported through the unstirred water layer to the gastrointestinal membrane thanks to the increased surface area and tiny droplets.^23,24 The lymphatic drug transport can also circumvent the first-pass effect.²⁶ and the droplets can spread quickly in both blood and lymph.²⁵ Furthermore, the SMEDDS formulation can be packed into gelatine capsules for use as a unit dosage container and kept at room temperature.

An isotropic, thermodynamically stable mixture of water, oil, surfactant (S), and co-surfactants (CoS) or co-solvents is called a micro emulsion. The ultra-low interfacial tension, often attained by combining two or more emulsifiers (S/CoS), is the primary factor that propels the creation of micro emulsions. One emulsifier, known as a surfactant, is primarily soluble in water, whilst the other, known as a co-surfactant, is primarily soluble in oil. For the generation of micro emulsions, co-surfactants lower the interfacial tension to an extremely low value.^27,28

MECHANISM OF SELF -EMULSIFICATION:

The precise mechanism underlying self-emulsification is yet unknown. It has been suggested that self-emulsification occurs when the energy needed to increase the dispersion's surface region above its favoured level is known as the entropy change. A basic emulsion preparation's free energy is directly related to the energy needed to create the most recent surface between the oil and water phases. The emulsion's two phases will gradually split in order to reduce the interfacial area, which is how the system's free energy is achieved.²⁹

COMPOSTION OF SMEDDS:

Oil/surfactant and co-surfactant physical mixtures of the formulation of SMEDDS in various ratios are employed in a variety of literature surveys. The SMEDDS preparation is made using the majority of the literature, which uses surfactant and co-surfactant mixtures (Smix) with oil in various ratios. The formulation of SMEDDS uses a number of components. is displayed in the following table.

TABLE: Classification of excipients used in formulation of SMEDDS

STABILITY:

(a) Temperature stability: the shelf life as a function of time and storage temperature is determined by visual inspection of the SMEDDS system at various intervals [29]. In order to verify the temperature soundness of tests, preparations are diluted using distilled water and maintained at a varied temperature range (room temperature, 2–8°C, or lower). Additionally, flocculation or precipitation is typically observed for any indications of phase separation.^30,31

(b) Centrifugation: the enhanced SMEDDS system is diluted with distilled water in order to evaluate the metastable system.²⁹. In order to check for any changes in the homogeneity of small-scale emulsions, the micro-emulsion is now centrifuged at 1000 rpm for 15 minutes at 0°C.^{32, 33, 34}

BIOPHARMACEUTICAL ASPECTS OF SMEDDS:

The widely held belief that lipids may improve bioavailability through a number of possible mechanisms, despite the fact that the biopharmaceutical elements of SMEDDS are still poorly understood is as follows: Changes (decrease) in gastric transit: -which slows transport to the absorption site and lengthens the dissolving time.

The enhancement in the solubility of effective luminal drugs: When lipids are present in the GI tract, the secretion of bile salts (BS) and endogenous billiard lipids, such as cholesterol (CH) and phospholipids (PL), increases. This results in the formation of intestinal mixed micelles, which increases the GI tract's capacity for solubilisation. But when supplied (exogenous) lipids are intercalated into these structures, either directly (if sufficiently polar) or indirectly (via digestion), the micellar structures inflate and their solubilisation capacity increases.

Lipids may either directly or indirectly boost bioavailability by reducing first-pass metabolism or by increasing the extent of intestinal lymphatic transport for highly lipophilic medicines.
Alteration to the GI tract's biochemical barrier function: -It is evident that some lipids and surfactants may decrease the amount of enterocyte-based metabolism and hence inhibit the activity of intestinal efflux transporters, as demonstrated by the p-glycoprotein efflux pump.

Shifts in the GI tract's physical barrier function: It has been demonstrated that a variety of lipid combinations, lipid digestion products, and surfactants boost permeability. To a large extent, however, passive intestinal permeability is not considered a significant obstacle to the bioavailability of most poorly water-soluble medications, especially those that are lipophilic.^35,36

DRUG PROPERTIES SUITABLE FOR SMEDDS

1. The dosage ought to be lower.
2. The medication must dissolve in oil.
3. A medication with a high melting point is not a good fit for SMEDDS.
4. A large log P value is desirable.^37,38

CONCLUSION

Self-Micro Emulsifying Drug Delivery Systems (SMEDDS) have become a strong and promising method for improving the oral bioavailability of medications that are not very water soluble, especially those that are classified as BCS Class II and IV. SMEDDS greatly enhance medication solubilisation, absorption, and bioavailability by promoting spontaneous emulsification in the gastrointestinal environment and generating fine oil-in-water emulsions.

SMEDDS can overcome a number of biopharmaceutical obstacles, such as enzymatic degradation, first-pass metabolism, and poor solubility, by using appropriate oils, surfactants, and co-surfactants. Lipid-based drug delivery systems prefer SMEDDS because of their scalability for industrial manufacture, thermodynamic stability, and formulation diversity.

SMEDDS have a lot of potential for use in pharmaceutical applications in the future, especially as there are more and more lipophilic drug candidates in the development pipeline. SMEDDS-based formulations will be more rationally designed and accepted by regulators with the support of additional research centred on mechanistic knowledge, excipient optimisation, and clinical evaluation.

ACKNOWLEDGEMENT

Authors acknowledge the immense help received from the scholars whose articles are cited and included in references of this manuscript. The authors are also grateful to authors and editors of all those articles, journals and books from where the literature for this article has been reviewed and discussed.

SOURCE OF FUNDING

This research received no external funding.

CONFLICT OF INTEREST

The authors deny any conflict of interest.

AUTHOR^’S CONTRIBUTION

Conceptualization: Mrs.Sucheta Moharana

Investigation: Sanjeeb Kar

Supervision: Prasanta Kumar Biswal

REFERENCES

1. Gursoy R.N., Benita S. Self-emulsifying drug delivery systems for improved oral delivery of lipophilic drugs: Biomedicine and Pharmacotherapy, 2004; 58:173-182.
2. Abdalla A., Klein S., Mader K. A new Self-emulsifying drug delivery system for poorly soluble drugs: European Journal of Pharmaceutical Sciences. 2008; 35:357-464.
3.  Amidon, G.L.; Lennernas, H.; Shah, V.P.; Crison, J.R. A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and In Vivo Bioavailability. Pharm. Res. 1995, 12, 413–420. [CrossRef] [PubMed]
4. Tran, P.; Park, J.-S. Recent Trends of Self-Emulsifying Drug Delivery System for Enhancing the Oral Bioavailability of Poorly Water-Soluble Drugs. J. Pharm. Investig. 2021, 51, 439–463. [CrossRef]
5. Nikolakakis, I.; Partheniadis, I. Self-Emulsifying Granules and Pellets: Composition and Formation Mechanisms for Instant or Controlled Release. Pharmaceutics 2017, 9, 50. [CrossRef] [PubMed]
6. Shah, M.K.; Khatri, P.; Vora, N.; Patel, N.K.; Jain, S.; Lin, S. Lipid Nanocarriers: Preparation, Characterization and Absorption Mechanism and Applications to Improve Oral Bioavailability of Poorly Water-Soluble Drugs. In Biomedical Applications of Nanoparticles; William Andrew Publisher: Norwich, NY, USA, 2019; pp. 117–147, ISBN 9780128165065.
7. Boyd, B.J.; Bergström, C.A.S.; Vinarov, Z.; Kuentz, M.; Brouwers, J.; Augustijns, P.; Brandl, M.; Bernkop-Schnürch, A.; Shrestha, N.; Préat, V.; et al. Successful Oral Delivery of Poorly Water-Soluble Drugs Both Depends on the Intraluminal Behavior of Drugs and of Appropriate Advanced Drug Delivery Systems. Eur. J. Pharm. Sci. 2019, 137, 104967. [CrossRef] [PubMed]
8. Porter, C.J.H.; Charman, W.N. Transport and Absorption of Drugs via the Lymphatic System. Adv. Drug Deliv. Rev. 2001, 50, 1–2. [CrossRef]
9. Charman WN, Rogge MC, Boddy AW, Berger BM. Effect of food and a monoglyceride emulsion formulation on danazol bioavailability. J. Clin. Pharmacol, 1993; 33: 381–6.
10. Welling PG. Effects of food on drug absorption. Ann. Rev. Nutr., 1996; 16: 383–415.
11. Zhu Y, Ye J, Zhang Q. (2020). Self-emulsifying drug delivery system improves oral bioavailability: role of excipients and physico-chemical characterization. Pharm Nanotechnol 8:290–301.
12. Leonaviciute G, Bernkop-Schn€urch A. (2015). Self-emulsifying drug delivery systems in oral (poly)peptide drug delivery. Expert Opin Drug Deliv 12:1703–16.
13. Amara S, Bourlieu
14.  C, Humbert L, et al. (2019). Variations in gastrointestinal lipases, pH and bile acid levels with food intake, age and diseases: possible impact on oral lipid-based drug delivery systems. Adv Drug Deliv Rev 142:3–15.
15. Page S, Szepes A. (2021). Impact on drug development and drug product processing. In: Solid state development and processing of pharmaceutical molecules: salts, cocrystals, and polymorphism. Vol. 79, 325–64. M. Gruss (Ed.).
16. Pouton, C.W. Lipid Formulations for Oral Administration of Drugs: Non-Emulsifying, Self-Emulsifying and “Self-Microemulsifying” Drug Delivery Systems. Eur. J. Pharm. Sci. 2000, 11, 93–98. [CrossRef]
17. Pouton CW. (2006). Formulation of poorly water-soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci 29:278–87.
18. Ramesh, B. J., Ramu, A., Vidyadhara, S., Balakrishna, T. (2019). Design and Evaluation of Telmisartan SMEDDS for Enhancing Solubility and Dissolution Rate. International Journal of Pharmaceutical Sciences and Nanotechnology, 12 (6), 4721– 4730. doi: http://doi.org/10.37285/ijpsn.2019.12.6.8
19. Hauss DJ. (2007). Oral lipid-based formulations. Adv Drug Deliv Rev 59:667–76.
20. Nanjwade B, Patel DJ, Udhani R, Manvi F. (2011). Functions of lipids for enhancement of oral bioavailability of poorly water-soluble drugs. Sci Pharm 879:705–27.
21. Mu¨llertz A, Ogbonnaa A, Ren S, Rades T. (2010). New perspectives on lipid and surfactant-based drug delivery systems for oral delivery of poorly soluble drugs. J Pharm Pharmcol 62:1622–36.
22. Eccleston GM. (2007). Emulsions and microemulsions. In: Swarbrick J, ed. Encyclopedia of pharmaceutical technology, vol. 3. New York: Informa Healthcare, 1548–65.
23. Gupta S, Kesarla R, Omri A. Formulation strategies to improve the bioavailability of poorly absorbed drugs with special emphasis on self-emulsifying systems. ISRN Pharm. 2013;2013:848043.
24. Shahnaz G, Hartl M, Barthelmes J, Leithner K, Sarti F, Hintzen F, et al. Uptake of phenothiazines by the harvested chylomicrons ex vivo model: influence of self-nanoemulsifying formulation design. Eur J Pharm Biopharm. 2011;79(1):171–80.
25. Grove M, Müllertz A, Nielsen JL, Pedersen GP. Bioavailability of seocalcitol: II: development and characterisation of self-microemulsifying drug delivery systems (SMEDDS) for oral administration containing medium and long chain triglycerides. Eur J Pharm Sci. 2006;28(3):233–42.
26. Amri A, Le Clanche S, Therond P, Bonnefont-Rousselot D, Borderie D, Lai-Kuen R, et al. Resveratrol self-emulsifying system increases the uptake by endothelial cells and improves protection against oxidative stress-mediated death. Eur J Pharm Biopharm. 2014;86(3):418–26.
27. Weerapol Y, Limmatvapirat S, Kumpugdee-Vollrath M, Sriamornsak P. Spontaneous emulsification of nifedipine-loaded self-nanoemulsifying drug delivery system. AAPS PharmSciTech. 2014; 1–9. doi: 10.1208/s12249-014-0238-0.
28. Parmar N, Singla N, Amina S, Kohli K. (2011). Study of co-surfactant effect on nano emulsifying area and development of lercanidipine loaded (SNEDDS) self-nanoemulsifying drug delivery system. Colloids Surf B 86:327–38.
29. Rahman A, Hussain A, Hussain S, et al. (2012). Role of excipients in successful development of self-emulsifying/microemulsifying drug delivery system (SEDDS/ SMEDDS). Drug Dev Ind Pharm 39:1–19.
30. Patel, M. J., Patel, S. S., Patel, N. M., Patel, M. M. (2010). A self-microemulsifying drug delivery system (SMEDDS). International Journal of Pharmaceutical Sciences Review and Research, 4 (3), 29–35. doi: http://doi.org/10.14843/jpstj.70.32
31. Dhumal, D. M., Akamanchi, K. G. (2018). Self-microemulsifying drug delivery system for camptothecin using new bicephalous heterolipid with tertiary-amine as branching element. International Journal of Pharmaceutics, 541 (1-2), 48–55. doi: http://doi.org/10.1016/j.ijpharm.2018.02.030
32. Mekjaruskul, C., Yang, Y.-T., Leed, M. G. D., Sadgrove, M. P., Jay, M., Sripanidkulchai, B. (2013). Novel formulation strategies for enhancing oral delivery of methoxyflavones in Kaempferia parviflora by SMEDDS or complexation with 2-hydroxypropyl-βcyclodextrin. International Journal of Pharmaceutics, 445 (1-2), 1–11. doi: http://doi.org/10.1016/j.ijpharm.2013.01.052
33. Kheawfu, K., Pikulkaew, S., Rades, T., Müllertz, A., Okonogi, S. (2018). Development and characterization of clove oil nanoemulsions and self-microemulsifying drug delivery systems. Journal of Drug Delivery Science and Technology, 46, 330–338. doi: http://doi.org/10.1016/j.jddst.2018.05.028
34. Ishak, R. A. H., Osman, R. (2015). Lecithin/TPGS-based spray-dried self-microemulsifying drug delivery systems: In vitro pulmonary deposition and cytotoxicity. International Journal of Pharmaceutics, 485 (1-2), 249–260. doi: http://doi.org/10.1016/ j.ijpharm.2015.03.019
35. Vasconcelos, T., Marques, S., Sarmento, B. (2018). Measuring the emulsification dynamics and stability of self-emulsifying drug delivery systems. European Journal of Pharmaceutics and Biopharmaceutics, 123, 1–8. doi: http://doi.org/10.1016/j.ejpb.2017.11.003
36. Christopher JH, Pouton CW, Jean FC, William NC. Enhancing intestinal drug solubilization using lipid-based delivery systems. Adv Drug Deliv Rev 2008; 60:673-91.
37. Lawrence M. J. and Rees G.D. Microemulsion-based media as novel drug delivery systems. Adv Drug Deliv Rev 2000; 45: 89-121.
38. Urvashi Goyal, Self- microemulsifying drug delivery system: a method for enhancement of bioavailability ,Int J Pharm Sci Res 2012:3(8);2441-2450.