INTRODUCTION:

Biopharmaceutical aspects of SMEDDS^5-7:

Biopharmaceutical aspects of SMEDDS although incompletely understood, the currently accepted view is that 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

· Increase in effective luminal drug solubility:

The presence of lipids in the GI tract stimulates an increase in the secretion of bile salts (BS) and endogenous biliary lipids including phospholipids (PL) and cholesterol (CH), leading to the formation of BS/PL/CH intestinal mixed micelles and an increase in the solubilization capacity of the GI tract. However, intercalation of administered (exogenous) lipids into these BS structures either directly (if sufficiently polar), or secondary to digestion, leads to swelling of the micellar structures and a further increase in solubilization capacity.

· Stimulation of intestinal lymphatic transport:

For highly lipophilic drugs, lipids may enhance extent of lymphatic transport and increase bioavailability directly or indirectly via a reduction in first-pass metabolism.

· Changes in the biochemical barrier function of the GI tract:

It is clear that certain lipids and surfactants may attenuate activity of intestinal efflux transporters, as indicated by the p-glycoprotein efflux pump and may also reduce extent of enterocyte based metabolism.

· Changes in the physical barrier function of the GI tract:-

Various combinations of lipids, lipid digestion products and surfactants have been shown to have permeability enhancing properties. For most part, however, passive intestinal permeability is not thought to be a major barrier to bioavailability of the majority of poorly water-soluble, and in particular, lipophilic drugs.

Drug Properties Suitable For SMEDDS^8,9

1. Dose should not be so high.

2. Drug should be oil soluble.

3. High melting point drug is poorly suited to SMEDDS.

4. Log P value should be high.

Excipients used in SMEDDS ^10-13:

The Self-Emulsifying Process Depends on:-

· The nature of oil-surfactant pair

· The surfactant concentration

· The temperature at which self-emulsification occurs.

Oils:-

The majorities of hydrophobic drugs are lipophilic in nature, and have greater solubility in triglycerides than in surfactants. It can facilitate self-emulsification and increase the fraction of lipophilic drug transported via the intestinal lymphytic system, thereby increasing absorption from the GI tract which avoids the first-pass metabolism of drugs, which definitely increase overall GI bioavailability of poorly water soluble drugs. Triglycerides such as medium chain and long chain with different degree of saturation have been used for the solvation of hydrophobic therapeutic agent in the design of SMEDDS.

For the formulation of self-emulsifying system both long chain triglycerides (LCT) eg. Soya bean, Sesame, Olive, Peanut, corn and rapeseed oils and medium chain triglycerides (MCT) eg. Fractionated Coconut oil and palm seed oil, triglycerides of caprylic/capric acid.eg. Miglyol 812, Captex 355are utilized, but as compared to LCT. The MCT have more capacity to solubilise lipophilic drugs, provides higher fluidity and good emulsification. In recent years much attention has been focused on MCT (C12- C18) for formulation of SEDDS. These MCT is nothing but a fractionated coconut oil. MCT are easy for digestion as compared to LCT, which convert to diglycerides, monoglycerides and free fatty acids. This conversion is facilitated by several gastric and intestinal enzymes like lipase, pancreatic lipase, etc.

Surfactant:

The surfactant molecule consists of polar or charged hydrophilic moieties as well as non-polar hydrophobic (lipophilic) moieties i.e. a surfactant compound must be amphiphilic in nature. Combinations of surfactants are used in the formulation of SMEDDS one of which is hydrophilic in nature while the remaining surfactant or surfactants being hydrophilic or hydrophobic. Surfactants used in SMEDDS are mainly (i) non-ionic, (ii) anionic, (iii) cationic or zwitter ionic Surfactants. Surfactants with lower lipophilic values are more hydrophobic and greater solubility in oils, whereas surfactants with higher HLB values are more hydrophilic and have greater solubility in aqueous mediums.

The non-ionic surfactants are generally considered to be those compounds having an HLB values greater than about 10 are providing fine, uniform emulsion. These non-ionic surfactants are less toxic than that of cationic and anionic surfactants. During the formulation design of any dosage form it is to be considered that excipients utilized in formulation should not cause any toxicity to patient. While in case of self-emulsifying system usual concentration of surfactant to form and maintain the emulsion state in GIT, ranged from 30- 60% w/w of the formulation, which is very high. Emulsifier of natural origin such as polyoxyl 35 castor oil (Cremophor EL), polyoxyl 40 castor oil (Cremophor RH40), polysorbate 80 (Tween 80) etc, are safer than that of synthetic surfactants. Surfactants are amphiphilic in nature and they can dissolve or solubilise relatively high amount of hydrophobic drug compounds.

Surfactant having a high HLB (8-18) are preferred for formation of o/w micro-emulsion whereas, surfactants having a low HLB (3-6) are preferred for formation of w/o micro-emulsion. anionic, cationic or zwitter ionic compound for which the HLB scale is not generally applicable. In most of literature it is revealed that, as the concentration of surfactant in self-emulsifying system increases, there is marked decrease in droplet size. Surfactants increase the permeability by interfering with lipid bi layer of single layer of epithelial cell membrane, which with unstirred aqueous layer, forms rate−limiting barrier to drug absorption/diffusion. Therefore, most drugs are absorbed via the passive transcellular route. Surfactants partition into cell membrane and disrupt structural organization of lipid bilayer leading to permeation enhancement. They also exert their absorption enhancing effects by increasing dissolution rate of drug.

Co-solvents and Co –Surfactant:

Co-solvents are used to dissolve large amounts of hydrophilic surfactants or the hydrophobic drug in the lipid base. These solvents sometimes play the role of the co surfactant in the micro-emulsion systems. Commonly used cosolvents include polyethylene glycol 400, propylene glycol, ethanol and glycerol diethylene glycol monoethyl ether (transcutol), polyoxyethylene, propylene carbonate, tetrahydrofurfuryl alcohol polyethylene glyco-lether (glycofurol), etc.

The physical state of these excipients at ambient room temperature is determined by their molecular weight. PEG ranging from 200 to 600 in molecular weight is liquid at ambient room temperature where those possessing molecular weight of 1000 or greater exit as thermo softening semi solid. Polymeric liquid and semi‐solid excipients, most of which are glycolic in nature and relatively non‐toxic, are used as solvents for formulating poorly water‐soluble drugs.

Generally co-surfactant of HLB value 10-14 is used with surfactant together to decrease the interfacial tension to a very small even transient negative value. At this value interface would expand to form fine dispersed droplets and subsequently adsorb more surfactant until their bulk condition is depleted enough to make interfacial tension positive again. This process is known as spontaneous emulsification. However, for many non-ionic surfactants it is not compulsory/mandatory to use co-surfactant in micro-emulsion. Selection of co-surfactant and surfactant is crucial not only to form formation of micro-emulsion but also to solubilization in micro-emulsions.

Such systems may exhibit some advantages over the previous formulations when incorporated in capsule dosage forms, since alcohol and other volatile co-solvents in conventional self-emulsifying formulations are known to migrate into shells of soft gelatin or hard sealed gelatin capsules resulting in precipitation of lipophilic drug. But drugs in alcohol free formulations may exhibit limited solubility. Hence, proper choice has to be made during selection of components.

Mechanisam of self-emulsification^14-16:

Different approaches have been reported in literature. No single theory explains all aspects of micro-emulsion formation. Formation of emulsion droplets was due to the formation of a complex film at the oil-water interface by surfactant and co-surfactant. According to theory of thermodynamic, emulsification takes place due to the entropy change that favours dispersion is greater than free energy required to increase surface area between oil and aqueous phases of dispersion. Process of emulsification involves change in free energy (ΔG) can be expressed by

ΔG =∑Nr²

ΔG - Free energy associated with the process (ignoring the free energy of the mixing),

N - Number of droplets

r- Radius of droplet

 - Interfacial energy with time.

Two phases of emulsion tend to be separate, in order to reduce interfacial area and subsequently, free energy of system. Therefore, emulsion is stabilized by emulsifying agents and forms a monolayer of emulsion droplets and ultimately reduces interfacial energy which acts as a barrier around oil droplets to prevent coalescen.

EVALUATION OF SMEDDS:^17-21

1. Dilution Study by Visual Observation:

Dilution study was done to study the effect of dilution on S-SMEDDS, because dilution may better mimic the condition of stomach after oral administration. In this method, S-SMEDDS (100 mg) was introduced into 100 mL of double distilled water in a glass beaker that was maintained at 37ºC and the contents mixed gently using a magnetic stirrer. The tendency to emulsify spontaneously and progress of emulsion droplets were observed with respect to time. The emulsification ability of S-SMEDDS was judged qualitatively “good” when clear micro-emulsion formed and “bad” when there was turbid or milky white emulsion formed after stopping of stirring.

2. Drug Content Determination:

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.

3. Droplet size:

This is a critical factor in self-emulsification process, since it determines the rate and extent of drug release as well as the stability of the emulsion. Photon correlation spectroscopy, microscopic techniques or a Coulter Nanosizer are mainly used for the determination of the emulsion droplet size. The reduction in droplet size to the values below 50μm leads to the formation of SMEDDSs, which are stable, isotropic and clear o/w dispersions.

4. Zeta potential measurement:

This is used to identify the charge of the droplets. In conventional SMEDDSs, the charge on an oil droplet is negative due to presence of free fatty acids. Zeta potential of solid S-SMEDDS were assessed by lesser light scattering technique using Malvern Zetasizer.

5. Thermodynamic stability studies:

For thermodynamic stability studies we have performed three main steps, they are-

● Heating cooling cycle:

Six cycles between refrigerator temperature 4°C and 45°C with storage at each temperature of not less than 48 h.

● Centrifugation:

Passed formulations are centrifuged at 3500 rpm for 30 min. Those formulations that does not show any phase separation are taken for the freeze thaw test.

● Freeze thaw cycle:

Freeze thawing was employed to evaluate the stability of formulations. Three freeze-thaw cycles between −21°C and +25°C with storage at each temperature for not <48 h was done for SMEDDS.

6. FTIR study:

FTIR studies were done to assess possible interaction among drug, oil, surfactant, co-surfactant.

7. Morphological analysis of S-SMEDDS :

The surface characteristics of solid-SMEDDS was determined by SEM.

8. In-vitro dissolution study:

To understand the characteristics of drug release from solid SMEDDS, an in- vitro drug release study was carried out in dissolution apparatus (USP type II).

REFERENCES:

1. Kavita Mehta, Ganesh Borade, Self-emulsifying drug delivery system formulation and evaluation, Int J Pharma and Bio Sci, 2011; 2(4): 398-412.

2. Mistry RB, Sheth NA. Review: Self-emulsifying drug delivery system. Int J Pharm 2011; 3(2): 23-28.

3. Mittal Pooja, Rana A.C., Lipid based self-microemulsifying drug delivery system for lipophilic drugs: An acquainted review, Inte Res J Pharm, 2011; 2(12): 75-80.

4. Kyatanwar AU, Jadhav KR, Kadam VJ. Self-microemulsifying drug delivery system (SMEDDS): review. J Pharm Res, 2010; 3(1):75-83.

5. K. Mohsin, A.A. Shahba, Lipid based self-emulsifying formulation for poorly water soluble drugs: An excellent opportunity, Indian J Pharma Edu Res, 2012; 46(2): 88-98.

6. Pouton CW. Formulation of Self-emulsifying drug delivery systems. Adv Drug Dev Rev 1997; 25:47-58.

7. Pouton CW. Lipid formulations for oral administration of drugs: non- emulsifying, self-emulsifying and ‘self –microemulsifying’ drug delivery systems. Eur J Pharma Sci, 2000; 11(2):93-98.

8. Gershanik T, Benita S. Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs. Eur J Pharma 2000; 50:179-88.

9. Pouton CW. Formulation of poorly water–soluble drugs for oral administration: physicochemical and physiological issues and the lipid formulation classification system. Eur J Pharm Sci, 2006; 29: 278-87.

10. Jessy Shaji, Newer approaches to self-emulsifying drug delivery system, Int J Pharma Pharma Sci 2010,2 (1), 37-42

11. Preethi Sudheer, Approaches to development of solid- self micron emulsifying drug delivery system: formulation techniques and dosage forms – a review, Asian J Pharm Life Sci, 2012; 2 (2), 2231 – 4423.

12. Sharma R. Solubility enhancement of lipophilic drugs-solid self emulsifying drug delivery systems. Int J Res Pharm Bio Sci 2013; 4(1):255-65.

13. Rajesh BV, Reddy TK, Srikanth G, Mallikarjun V, Nivethithai P. Lipid Based Self Emulsifying Drug delivery system (SEDDS) for Poorly Water-Soluble Drugs: A Review J Pharma Tech 2010; 2(3):47-55.

14. Craig DQM. The use of self-emulsifying systems as a means of improving drug delivery. B T Gattefosse 1993; 86:21–31.

15. Constantinides PP. Lipid micro emulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects. Pharm Res 1995; 12:1561–72.

16. Schulman JH, Stoeckenius W, Prince LM. Mechanism of formation and structure of micro-emulsions by electron microscopy. J Phys Chem 1959; 63: 1677–80.

17. Vandana B, Patravale, Abhijit A, Amit A, et. al. Oral self-microemulsifying system: potential in DDS, Pharm Tech, Express Pharma Pulse Special Feature. 2003; 29: 44-48.

18. Chen Oral dosage self emulsifying formulations of pyranone protease inhibitors. United States Patent 6,555,558, April 29, 2003.

19. Christopher JH, Pouton CW, Jean FC, William NC. Enhancing intestinal drug solubilisation using lipid-based delivery systems. Adv Drug Deliv Rev 2008; 60:673-91.

20. Lawrence M. J. and Rees G.D. Microemulsion-based media as novel drug delivery systems. Adv Drug Deliv Rev 2000; 45: 89-121.

21. Urvashi Goyal, Self- microemulsifying drug delivery system: a method for enhancement of bioavailability, Int J Pharm Sci Res 2012:3(8); 2441-2450.

Received on 13.05.2016 Accepted on 04.06.2016

Asian J. Pharm. Tech. 2016; 6 (3): 155-158.

DOI: 10.5958/2231-5713.2016.00022.2