INTRODUCTION:

If any new formulation has to success in the pharmaceutical market they should fulfil all these parameter like stability, bioavailability, cost of product and patient compliance. If the formulation fails to comply any one of the parameter then product may get fail to acquire capital market in the pharmaceutical field. Several strategies have been adopted for to overcome such a mentioned problem by various techniques. For the therapeutic delivery of lipophillic active moieties (BCS class II drugs), lipid based formulations are inviting increasing attention.

Currently a number of technologies are available to deal with the poor solubility, dissolution rate and bioavailability of insoluble drugs. Self micro emulsifying drug delivery system (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 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.

More than 60% of potential drug products suffer from poor water solubility. This frequently results in potentially important product not reaching the market or not achieving their full potential. Pharmaceutical industry is quick in realizing the importance of solubility and dissolution rate in bioavailability and good deal of research has been done in this area. In recent years, much attention has been paid to self microemulsifying drug delivery system (SMEDDS), which have shown lots of reasonable success in improving oral bioavailability of poorly soluble drugs. One of the traditional approaches used to improve solubility of a poorly water soluble molecule without losing its biological activity is by producing various salt forms. Prodrug approach has also resulted in improved solubility.

NEED FOR SMEDDS^[1,2]

BCS class II or class IV compounds, when given orally to the gastrointestinal tract are typically dissolution rate-limited i.e. the absorption rate from the gastrointestinal (GI) lumen is controlled by dissolution.13

There is currently no single or simple solution to the challenge. Different formulation approaches can be used for this like, 13

Modification of the physicochemical properties, such as

· Salt formation,

· Particle size reduction (micronization) of the compound,

· Solid dispersion,

· Complexation with cyclodextrins,

Use of Permeation enhancers.

Indeed, in some selected cases, these approaches have been successful. However, these methods have their own limitations.

Advantages of SMEDDs^[11]:

1. Irritation caused by prolonged contact between the drug and the wall of the GIT can be surmounted by the formulation of SMEDDs as the microscopic droplets formed help in the wide distribution of the drug along the GIT and these are transported quickly from the stomach.

2. Upon dispersion in water, these formulations produce fine droplets with enormous interfacial area due to which the easy partition of the drug from the oil phase into the aqueous phase is possible which cannot be expected in case of oily solutions of lipophilic drugs.

3. SMEDDs are advantageous over emulsions in terms of the stability because of the low energy consumption and he manufacturing process does not include critical steps.

4. Simple mixing equipment is enough to formulate SMEDDs and time required for preparation is also less compared to emulsion.

5. Poor water soluble drugs which have dissolution rate limited absorption can be absorbed efficiently by the formulation of SMEDDs with consequent stable plasma-time profile.

6. Constant plasma levels of drug might be due to presentation of the poorly water soluble drug in dissolved form that bypasses the critical step in drug absorption, that is, dissolution.

7. Along with the lipids, surfactants that are commonly used in the formulation of SMEDDs like Tween 80, Spans, Cremophors (EL and RH40), and Pluronics are reported to have inhibitory action on efflux transporters which help in improving bioavailability of the drugs which are substrates to the efflux pumps. Drugs which have propensity to be degraded by the chemical and enzymatic means in GIT can be protected by the formulation of SMEDDs as the drug will be presented to the body in oil droplets.

Disadvantages of SMEDDS^[8]

1. One of the obstacles for the development of SMEDDs and other lipid-based formulations is the lack of good predicative in vitro models foe assessment of the formulations.

2. Traditional dissolution methods do not work, because these formulations potentially are dependent on digestion prior to release of the drug.

3. This in vitro model needs further development and validation before its strength can be evaluated. 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.

4. The drawbacks of this system include chemical instabilities of drugs and high surfactant concentrations in formulations (approximately 30-60%) which irritate GIT. Moreover, volatile co solvents in the conventional self-micro emulsifying formulations are known to migrate into the shells of soft or 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 solvents. Formulations containing several components become more challenging to validate.

Composition of SMEDDS^[7-13]:

The SMEDDS composed of the oil and surfactant. The ratio of concentration of the oil and surfactant depends upon the solubility of the drug and self emulsifying ability. The nature of oil, concentration of surfactant and the temperature at which self emulsification occur is also important during the formulation of SMEDDS. Preformulation studies are carried out for the selection of oil, surfactant and co-surfactant as these are specific for a particular SMEDDS. First we govern solubility of drug in various oils and surfactant/co-surfactant then prepare a series of SMEDDS system containing drug in various oils and surfactants/co-surfactants. By constricting the Pseudo-ternary phase diagram we identify the efficient self -emulsification region.

A. Oils:

One of the most important excipients because oil can solubilise the lipophilic drug in a specific amount and it can facilitate self emulsification and increase the fraction of lipophilic drug transported via the intestinal lymphatic system, mainly the long chain and medium chain triglycerides are use. The concentration of oil present in SMEDDS is about the 40 to 80 % the modified and hydrolyzed vegetable oils widely because they show the more solubility and good self emulsifying property. Solvent capacity for less hydrophobic drugs can be improved by blendingtriglycerides with mono- and di-glycerides

B. Surfactants:

The surfactant is the important for the solubilisation of the drug in the oil and they commonly use as the emulsifier in this system. The various surfactants are using in this system mainly the non-ionic surfactants. The non-ionic surfactants have the ability to from the self emulsification in gastric medium also the non ionic surfactant having the less toxicity. The non-ionic surfactant cause the reversible changes in the permeability of the intestinal lumen. The concentration of surfactant is most important parameter because the self emulsification of SMEDDS is depends up on the concentration ratio of oil and surfactant. The concentration of surfactant is about the 30 to 60 % in SMEDDS and the HLB value of non ionic surfactant is about >12. The large quantity of the surfactant may cause the gastric irritation. The droplet size depends up on the concentration of surfactant. The mean droplet size is increase with increasing the surfactant concentration. This could be attributed to the interfacial disruption elicited by enhanced water penetration into the oil droplet mediated by the increased surfactant concentration and leading to ejection of oil droplets into the aqueous phase. The surfactants used in these formulations are known to improve the bioavailability by various mechanisms including: improved drug dissolution, increased intestinal epithelial permeability, increased tight junction permeability.

C. Co-surfactant:

For the fabrication of an optimum SMEDDS, high concentration of surfactant is required in order to reduce interfacial tension sufficiently, which can be harmful, so co-surfactants are used to shrink the concentration of surfactants. Co-surfactants together with the surfactants afford the sufficient litheness to interfacial film to take up different curvatures required to form micro-emulsion over a wide range of composition. Selection of proper surfactant and co-surfactant is necessary for the efficient design of SMEDDS and for the solubilisation of drug in the SMEDDS. Organic solvents like ethanol, propylene glycol, polyethylene glycol are able to dissolve large amount of either drug or hydrophilic surfactant in lipid base and are suitable for oral delivery, so they can be used as co-surfactant for SMEDDS. Alternately alcohols and other volatile co-solvents show a disadvantage that by evaporation they get entered into soft/hard gelatin capsule shells resulting in precipitation of drug. On the other hand formulations which are free from alcohols have limited lipophilic drug dissolution ability. Hence, appropriate choice of components has to be made for formulation of efficient SMEDDS. Hydrophilic co-surfactants are preferably alcohols of intermediate chain length such as hexanol, pentanol and octanol, which are known to reduce the oil/water interface and allow the spontaneous formulation of micro emulsion.

Preparations of SMEDDS formulations^[3-6]:

SMEDDS was prepared according to recently reported method. Variable proportions of oil, surfactant and co-surfactant were added into a 10 ml screw capped glass tube, and the components were mixed by gentle stirring. After complete dissolution, SMEDDS, a clear and transparent solution, was obtained. Based on the results of above experiment and the reported concentration scope of three ingredients forming SMEDDS, the contents of surfactant, co-surfactant and oil were chosen at the range of 30-65%, 30-65% and 5-40%, respectively, in order to obtain the optimal formulation of SMEDDS. Now a days for optimization and design of SMEDDS the surface methodology, modified simplex method and box- bechnken design optimization techniques use.

Mechanism of SMEDDS^[4]:

No single theory explains all aspects of micro emulsion formation. Schulman et al. considered that the spontaneous formation of micro emulsion droplets was due to the formation of a complex filmat the oil‐water interface by the surfactant and co‐surfactant. Thermodynamic theory of formation of micro emulsion explains that emulsification occurs, when the entropy change that favour dispersion is greater than the energy required to increase the surface area of the dispersion[17] and the free energy (ÄG) is negative. The free energy in the micro emulsion formation is a direct function of the energy required to create a new surface between the two phases and can be described by the equation: ÄG = S N a r 2 óð Where, ÄG is the free energy associated with the process (ignoring the free energy of the mixing), N is the number of droplets of radiusr and ó are presents the interfacial energy. With time, the two phases of the emulsion tend to separate to reduce the inter facial area, and subsequently, the free energy of the system decreases. Therefore, the emulsion resulting from aqueous dilution are stabilized by conventional emulsifying agents, which forms a monolayer around the emulsion droplets, and hence, reduce the interfacial energy, as well as providing a barrier to prevent coalescence.

Evaluation of SMEDDS^[10,16]:

1. Visual assessment may provide important information about the self‐emulsifying property of the SMEDDS and about the resulting dispersion. Estimation of the increased drug dissolution and absorption from large surface area afforded by the emulsion. Inhibit gastric motility by oil / lipid phase of emulsion allows more time for dissolution and absorption of drug from lipid phase. Fatty acids are distributed between other aqueous solution emulsion droplets and the micelles (formed by bile salt) Monoglycerides along with water insoluble components such as vitamins, lipophillic drugs are moved into the micelles, which diffuse through gut content to intestinal mucosa. Short chain fatty acids along with hydrophilic drug are diffused directly to portal supply, while longer fatty acids are utilized in chylomicron formation. Once monoglycerides along with lipophillic drugs are transported into intestinal mucosa, chylomicron synthesis takes place and are released into lymphatic’s efficiency of the self‐emulsification can be done by evaluating the rate of emulsification and particle size distribution. Turbidity measurement to identify efficient self‐emulsifying can be done to establish whether the dispersion has reached equilibrium rapidly and in reproducible time.

2. Droplet polarity and droplet size are important emulsion characteristics. Polarity of oil droplets is governed by the HLB value of oil, chain length and degree of unsaturation of the fatty acids, the molecular weight of the hydrophilic portion and concentration of the emulsifier. A combination of small droplets and their appropriate polarity (lower partition coefficient o/w of the drug) permit acceptable rate of release of the drug. Polarity of the oil droplets is also estimated by the oil/water partition coefficient of the lipophilic drug.

3. Size of the emulsion droplet is very important factor in self emulsification/ dispersion performance, since it determine the rate and extent of drug release and absorption. The Coulter nanosizer, which automatically performs photon correlation analysis on scattered light, can be used to provide comparative measure of mean particle size for such system. This instrument detects dynamic changes in laser light scattering intensity, which occurs when particle oscillates due to Brownian movement. This technique is used when particle size range is less than 3μm; a size range for a SMEDDS is 10 to 200 nm.

4. For sustained release characteristic, dissolution study is carried out for SEMDDS. Drugs known to be insoluble at acidic pH can be made fully available when it is incorporated in SMEDDS.

CONCLUSION:

Self‐Micro Emulsifying Drug Delivery Systems appear to be unique and industrially feasible approach to overcome the problem of low oral bioavailability associated with the lipophillic drugs. As there is increase in oral drug absorption of BCS II class drugs, so we can say it is one of the method for enhancing oral bioavailability of drug.Further research in developing SMEDDS with surfactants of low toxicity and to develop in vitro methods to better understand the in vivo fate of these formulations can maximize the availability of SMEEDS in market.

REFERENCES:

1. Brijesh Chaudhary, Kapil Maheshwari. Self-emulsifying drug delivery system: a novel approach for enhancement of bioavaibility: Journal of Pharmaceutical Science and Biosceintific Research; (2011) 31-36.

2. Bose S, and Kulkarni P.K., Self emulsifying drug delivery systems: A Review, Ind. J. Phar. Edu.2002, 36(4), 184‐190.

3. J.-L. Tang, J. Sun, and Z.-G. He, “Self-emulsifying drug delivery systems: strategy for improving oral delivery of poorly soluble drugs,” Current Drug Therapy, vol.2(1), 85-93, 2007.

4. Chaudhary B, Maheshwari K. Self-emulsifying drug delivery system: a novel approach for enhancement of bioavailability, J Pharm. Sci. Biosci. 2011; 31-36.

5. Patil P, Joshi P, Paradkar A, Effect of formulation variables on preparation and evaluation of gelled selfemulsifying drug delivery system (SEDDS) of ketoprofen, AAPS Pharm SciTech, 2004, 5, E42.

6. Anand U. Kyatanwar , Kisan R. Jadhav, Vilasrao J. Kadam. Self micro-emulsifying drug delivery system (SMEDDS): Journal of Pharmacy Research; 2010, 75-83.

7. M. R. A. Alex, A. J. Chacko, S. Jose, and E. B. Souto, “Lopinavir loaded solid lipid nanoparticles (SLN) for intestinal lymphatic targeting,” European Journal of Pharmaceutical Sciences, Vol.42 (1-2) 2011,11–18.

8. G. Sharma, K. Wilson, C. F. Van derWalle, N. Sattar, J. R. Petrie, and M. N. V. R. Kumar, “Microemulsions for oral delivery of insulin: design, development and evaluation in streptozotocin induced diabetic rats,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 76(2) 2010,159–169.

9. Anand U. Kyatanwar, Kisan R. Jadhav, Vilasrao J. Kadam, "Self micro-emulsifying drug delivery system (SMEDDS)”, Journal of Pharmacy Research,Vol.3(1),2010,75-83.

10. Sachan A. Khatri, S. B Kasture. Self-Eumlsifying Drug Delivery System A Novel Approach for enhancement of Bioavalibility: Int. J of PharmTech Research; 2010, 1738-1745.

11. J. A. Y´a˜nez, S. W. J. Wang, I. W. Knemeyer, M. A. Wirth, and K. B. Alton, “Intestinal lymphatic transport for drug delivery,” Advanced Drug Delivery Reviews, vol. 63 (10 11), 2011: 923–942.

12. Lawrence MJ, Rees GD, Microemulsion-based media as novel drug delivery system, Advanced Drug Delivery Review, 45, 2000, 89-121.

13. Emad B. Basalious, Nevine Shawky; SMEDDS containing bioenhancers for improvement of dissolution and oral absorption of lacidipine. I: Development and optimization; International Journal of Pharmaceutics 391,2010, 203–211.

14. K. Kohli, S. Chopra, D. Dhar, S. Arora, and R. K. Khar, “Self emulsifying drug delivery systems: an approach to enhance oral bioavailability,” Drug Discovery Today,vol.15, (21-22),2010, 958–965.

15. Shukla J.B., Koli A.R., Ranch K.M., Parikh R.K., Self emulsifying drug delivery system, An International Journal of Pharmaceutical Science 2010; 1(2): 13-33.

16. V. Borhade, H. Nair, and D. Hegde, “Design and evaluation of self-microemulsifying drug delivery system (SMEDDS) of tacrolimus,” AAPS PharmSciTech, vol.9(1),2008, 13–21.