RECENT TREDNS AND FUTURE PROSPECTS FOR SELF EMULSIFYING DRUG DELIVERY SYSTEM

About Authors:
Singh khushboo, Sharma monica,
Ram gopal college of pharmacy,
Gurgaon

ABSTRACT
Approximately 40% of new drug candidate have poor water solubility and oral delivery of such drug is frequently associated with implications of low bioavailabilty,high inter and intra subject variability, lack of dose proportionality. Bioavalibilty of lipophilic drug can be solved by formation of self emulsifying drug delivery system.SEDDS are belongs to lipid formulation and size range is from 100nm[SEDDS] less than 50nm[SMEDDS] and contain a isotropic mixture of oil, surfactant and co surfactant which are emulsified in aqueous media under condition of gentle agitation. The theory behind dissolution rate improvement by means of SEDDS is the spontaneous development of emulsion in GIT with mild agitation provide by gastric motility, which present the drug in solubilized form,small size of formed droplet provided a large inter facial area for absorption,due to small globule size thAT can be easily absorb through lymphatic pathway, thereby passing hepatic pathway.

Reference Id: PHARMATUTOR-ART-1174

INTRODUCTION
Self emulsifying system have gained exposure of their ability to increase solubility and bio availability of poorly soluble drug.SEDDS are isotropic mixture of oil, surfactant and co-solvent.SEDDS produce fine oil in water emulsion when introduced in aqueous media  under gentle agitation(1).

There are two type of SELF system

Self emulsifying drug delivery system[SEDDS]

Self micro-emulsifying drug delivery system[SMEDDS]

ADVANTAGE OF SELF EMULSIFYING DRUG DELIVERY SYSTEM OVER CONVENTIONAL SYSTEM
*  Protection of sensitive drug substance.
*  More consistent drug absorption(3)
*  Protection of drug from gut environment.
*  Control of delivery profile
*  High drug loading efficiency

DISADVANTAGE OF SELF EMULSIFYING DRUG DELIEVRY SYSTEM
*    Chemical instabilities of drugs and high surfactant concentrations(4)
*     The large quantity of surfactant in self-emulsifying formulations (30-60%) irritates GIT.                Consequently, the safety aspect of the surfactant vehicle had to be considered.
*     Moreover, volatile co solvents in the conventional self-emulsifying formulations are known to migrate into the shells of soft or hard gelatin capsules, resulting in the precipitation of the  lipophilic drugs.
*     Lack of in vitro model for the assessment of  the formulations.

COMPOSITON OF SEDDS
The self emulsifying depends on(5):
*    The nature of oil surfactant pair.
*    The surfactant concentration.
*    The temperature at which self emulsification occur.

Oils. Oils can solubilize the lipophilic drug in a specific amount. It is the most important excipient because it can facilitate self-emulsification and increase the fraction of lipophilic drug transported via the intestinal lymphatic system, thereby increasing absorption from the GI tract (6). Long-chain triglyceride and medium-chain triglyceride oils with different degrees of saturation have been used in the design of SEDDSs. Modified or hydrolyzed vegetable oils have contributed widely to the success of SEDDSs owing to their formulation and physiological advantages (7). Novel semisynthetic medium-chain triglyceride oils have surfactant properties and are widely replacing the regular medium- chain triglyceride (6).

Surfactant. Nonionic surfactants with high hydrophilic–lipophilic balance (HLB) values are used in formulation of SEDDSs (e.g., Tween, Labrasol, Labrafac CM 10, Cremophore, etc.). The usual surfactant strength ranges between 30–60% w/w of the formulation in order to form a stable SEDDS. Surfactants have a high HLB and hydrophilicity, which assists the immediate formation of o/w droplets and/or rapid spreading of the formulation in the aqueous media. Surfactants are amphiphilic in nature and they can dissolve or solubilize relatively high amounts of hydrophobic drug compounds. This can prevent precipitation of the drug within the GI lumen and for prolonged existence of drug molecules (8).

Cosolvents. Cosolvents like diehylene glycol monoethyle ether (transcutol), propylene glycol, polyethylene glycol, polyoxyethylene, propylene carbonate, tetrahydrofurfuryl alcohol polyethylene glycol ether (Glycofurol), etc., may help to dissolve large amounts of hydrophilic surfactants or the hydrophobic drug in the lipid base. These solvents sometimes play the role of the cosurfactant in the microemulsion system.

FORMULATION OF SEDDS
With a large variety of liquid or waxy excipients available, ranging from oils through biological lipids, hydrophobic and hydrophilic surfactants, to water-soluble cosolvents, there are many different combinations that could be formulated for encapsulation in hard or soft gelatin or mixtures which disperse to give fine colloidal emulsions (11). The following should be considered in the formulation of a SEDDS:

ØThe solubility of the drug in different oil, surfactants and cosolvents.

ØThe selection of oil, surfactant and cosolvent based on the solubility of the drug and the preparation of the phase diagram (12).

ØThe preparation of SEDDS formulation by dissolving the drug in a mix of oil, surfactant and cosolvent.

The addition of a drug to a SEDDS is critical because the drug interferes with the self-emulsification process to a certain extent, which leads to a change in the optimal oil–surfactant ratio. So, the design of an optimal SEDDS requires preformulation-solubility and phase-diagram studies. In the case of prolonged SEDDS, formulation is made by adding the polymer or gelling agent (13).

NOW YOU CAN ALSO PUBLISH YOUR ARTICLE ONLINE.

SUBMIT YOUR ARTICLE/PROJECT AT articles@pharmatutor.org

Subscribe to Pharmatutor Alerts by Email

FIND OUT MORE ARTICLES AT OUR DATABASE

MECHANISM OF SELF EMULSIFICATION

Self-emulsification occur when the entropy change that favors dispersion than the energy require to increase the surface area of the dispersion.

                        DG =  S N_i p r_i 2s

DG=free energy associated with the process

N=no.of droplets,R=radius of droplet,S=interfacial energy

CHARACTERIZATION
The primary means of self emulsification assessment is visual evaluation. the efficiency of self emulsification could be estimated by deterring rate of emulsification, droplet size distribution and turbidity measurements

Visual assessmentThis may provide important information about the self emulsifying and micro emulsifying property of mixture and resulting dispersion

Turbidity measurementThis is to identify efficient self emulsification by establishing whether the dispersion reaches equilibrium rapidly and in a reproducible tine

Droplet sizeThis is  crucial factor in self emulsification performance because it determines the rate and extent of drug release as well as  stability of the emulsion, photon correlation spectroscopy,microscopic technique mainly used or emulsion droplet size.

Zeta potential measurementThis is to identify the charge of droplets, in conventional SEDDS,the charge on the droplet is negative due to presence of fatty acids.

BIOPHARMACEUTICAL ASPECTS
The ability of lipids and/or food to enhance the bioavailability of poorly water soluble drugs has been comprehensively reviewed and the interested reader is directed to these references for further details. Although incompletely understood, the currently accepted view is that lipids may enhance bioavailability via a number of potential mechanisms including the following. [29]

Ø   Alterations (reduction) in gastric transit, thereby slowing delivery to the absorption site and increasing the time available for dissolution. [30]

Ø   Increases in effective lumenal 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 phospholipid (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. [31]

Ø   Stimulation of intestinal lymphatic transport: For highly lipophilic drugs, lipids may enhance the extent of lymphatic transport and increase bioavailability directly, or indirectly via a reduction in first-pass metabolism. [32],[33],[34],[35]

Ø   Changes in the biochemical barrier function of the GI tract: It is clear that certain lipids and surfactants may attenuate the activity of intestinal efflux transporters, as indicated by the p-glycoprotein efflux pump, and may also reduce the extent of enterocyte-based metabolism. [36],[37],[38],[39]

Ø  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 the most part, however, passive intestinal permeability is not thought to be a major barrier to the bioavailability of the majority of poorly water soluble, and in particular, lipophilic drugs. [8]

FACTORS AFFECTING SMEDDS FORMULATION
Ø    Drugs which are administered at very high dose are not suitable for SMEDDS,unless they exhibit extremely good solubility in at least one of the components of SMEDDS,preferably lipophilic phase.The drugs exhibit limited solubility in water and lipids are most difficult to deliver by  SMEDDS(9).

Ø    The polarity of lipid phase is one of the factors that govern the release from drug from the microemulsion.HLB,chain length degree or unsaturation of the fatty acid,molecular weight of the hydrophilic portion and concentration of the emulsifier govern polarity of the droplets.In fact,the polarity reflects the type of forces involved.The high polarity will promote rapid rate of release of the drug into the aqueous phase.sang-cheol chi et al.who observed that the rate of release of idebenone from SMEDDS is dependent upon the polarity f the oil phase used.The highest release was obtained with the formulation that had oily phase with highest polarity(10).

Ø    The ability of SMEDDS to maintain the drug in solubilized of the drug in oily phase.if the surfactant or co-surfactant is contributing to  greater extent for drug solubilization,here could be a risk of precipitation,as dilution of SMEEDS will lead to lowering of solvent capacity of surfactant or co-surfactant(11).

APPLICATION OF SELF EMULSIFYING DRUG DELIVERY SYSTEM

FUTURE ASPECTS
Supersaturable SEDDS{S-SEDDS}
The high surfactant level typically present in SEDDS formulation can lead to gi side effects and a new class of supersaturable formulation including supersaturable SEDDS{S-SEDDS} formulation have been designed and developed to reduce the surfactant side effects and achieve rapid absorption of poorly soluble drugs. The S-SEDDS approach is to generate a protracted supersaturated solution of the drug when the formulation is released from an appropriate dosage form into an aqueous supersaturation in intended to increase the thermodynamic activity to the drug beyond its solubility limit and,therefore,to result in an increased driving force fir transit into and across the biological barrier(16).

Solid SEDDS
SEDDS are normally prepared as liquid dosage from that can be administer in soft gelatin capsules,which have some disadvantages especially in the manufacturing process.An alternative method is the  incorporation f liquid self-emulsifying ingredients into a  powder in order to create a solid dosage for{tablets,capsules}

Improvement in solubility and bioavailability
If dug is formulated in SEDDS,then it increases the solubility because it circumvents the dissolution step in case of class ii drug(low solubility/high permeability).in SEDDS,the lipids matrix interacts readily with water,forming a fine particulate oil-in-water emulsion.the emulsion droplets will deliver the drug to the gastrointestinal  mucosa in the dissolved staet readily accessible for absorption,therefore increase in AUC I.e bioavailabilty and  Cmax is observed with many drugs when presented in SEDDS(17).

RECENT APPROACHES S IN SELF EMULSIFYING DRUG DELIVERY SYSTEM
Ø  SEDDS of coenzyme Q10 was prepared and this resulted in enhanced bioavailability and reduced toxicity.

Ø   Lipophilic compound WIN 54954 was formulated as SEDDS in triglyceride oil/non-ionic surfactant mixtures and resulted in improved reproducibility of the plasma profile in terms of Cmax and Tmax. (18

Ø  Self-microemulsifying drug delivery system (SMEDDS) of simavastin was developed to enhance its oral bioavailability. This study illustrated the potential use of SMEDDS for the delivery of hydrophobic compounds. (19)

Ø  A novel SEDDS of PTX (used for the treatment of solid tumors) was prepared and it was found that SEDDS was chemically stable for at least 1 year when kept as two part formulation and also the drug loading was increased by approximately fivefold. Compared to marketed i.v. formulation, the excipient presented a significantly reduced cytotoxicity and led to a stable microemulsion. (20)

Ø   An antimalarial drug, Halofantrine, was prepared as SEDDS and SMEDDS and resulted in an eightfold improvement in absolute oral bioavailability relative to previous data of the solid. (21)

Ø  Enhanced bioavailability upto 1.88 of silymarin was achieved by SMEDDS.(22)

Ø   Using SEDDS, self-nanoemulsified drug delivery system (SNEDDS) of ubiquinone was prepared and the study revealed that SNEDDS overcame the drawbacks of the traditional emulsified system, such as low solubility and irreversible precipitationof the active drug in the vehicle with time.(23)

Ø  The two novel SMEDDSs containing Labrasol with different dilutions on tight junction were studied and found that Labrasol at a concentration of 0.1 and 1% was shown to increase the permeability of mannitol by 4.6-fold and 33.8-fold, respectively.(24)

Ø   The solid self-emulsifying system (SES) was used in the delivery of diclofenac and results indicated that diclofenac could be comfortably administered in the form of self-emulsifying tablets using goat fat and Tween 65 admixtures.

Ø   SEDDS containing ketoprofen was formulated as sustained release dosage form and it was    found that drug release was increased.

CONCLUSION
Self-emulsifying drug delivery systems are a promising approach for the formulation of drug compounds with poor aqueous solubility. The oral delivery of hydrophobic drugs can be made possible by SEDDSs, which have been shown to substantially improve oral bioavailability. With future development of this technology, SEDDSs will continue to enable novel applications in drug delivery and solve problems associated with the delivery of poorly soluble drugs.

REFERANCES
1.N.H. Shah,M.T Carvejal,C.I Patel,N.H. Infeld,Int J Pharm.1994,106
2.Poton CW Formulation of self emulsifying drug delivery systems,Advanced Drug Delievry REVIEW 1997:25:47-58
3.A Patel,GH Chaulang,SS Mutha and SR Handicap,Research J Pharma and Tech,2008,1(4),313
4.S.M. Khoo et al., "Formulation design and bioavailability assessment of lipidic self-emulsifying formulation " International Journal of Pharmaceutics”167, 155–164 (1998).
5.R.N. Gursoy and S. Benita, "Self-emulsifying drug delivery systems for improved oral delivery of lipophilic drugs," Biomedicine and Pharmacotherapy 58,173-182 (2004).
6. P.P. Constantinides, "Lipid microemulsion for improving drugs dissolution and oral absorption: physical and biopharmaceutical aspects," Pharm Res. 12, 1561-1572 (1995).
7.S.M. Khoo et al., "Formulation design and bioavailability assessment of lipidic self-emulsifying formulation of halofanitrine," International Journal of Pharmaceutics “67, 155–164 (1998).
8.N.H. Shah et al., "Self-emulsifying drug delivery systems (SEDDS) with polyglycolized glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs." Int. J. Pharm. 106, 15–23 (1994)
9. S.M. Khoo et al., "Formulation design and bioavailability assessment of lipidic self-emulsifying formulation of halofantrine," International Journal of Pharmaceutics 167, 155–164 (1998).
10. N.H. Shah et al., "Self-emulsifying drug delivery systems (SEDDS) with polyglycolized glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs." Int. J. Pharm. 106, 15–23 (1994).
11. J.R. Crison and G.L. Amidon, "Method and formulation for increasing the bioavailability of poorly water-soluble drugs," US Patent No. 5,993,858, issued November 30, 1999.
12. N. Farah, J.P. Laforet and J. Denis, "Self Micro Emulsifying Drug Delivery Systems for improving dissolution of drugs: In vitro evaluations," presented by Gattefosse Patented Technology at the AAPS Annual Meeting in San Diego, November 1994.
13. S. Nazzal and M.A. Khan, "Controlled release of a self-emulsifying formulation from a tablet dosage form: Stability assessment and optimization of some processing parameters," International Journal of Pharmaceutics 315, 110–121 (2006).
14.Patil P oshiP,radkar A effect of formulation variable in preparation and evaluation of gelled self emulsifying drug deliverysystem of ketoprofen,AAPS pharamsciTech 2004:5[3]:1-8
15.Ianian W et al Preparation and evaluation of SEDDS and SMEEDS containing Carvedolol,drug development an dindustrial pharmacy 2005:31:785-794
16.Gao p,Rush BD,Pfund WP.Journal of Pharmaceutical Sciences 2003:92:2386-2398
17.Patel Pa,Chaulang GM,Akolkotkar A,Mutha SS,”Self Emusifying Drug Delivery System” A Review”Research J Pharm. And Tech.2008(14)13-323
18.Wakerley MG, Pouton CW, Meakin BJ, Morton FS. Self-emulsification of vegetable surfactant mixtures: A proposed mechanism of action. American Chem Soc Symp Ser 1986;311:242-55..  
19.Ishida M, Tawa R, Shibata N, Takada K. Oral solid gentamicin preparation using emulsifier and adsorbent. J Control Release 2005;105:23-31.  [PUBMED]
20.Verreck G, Brewster ME. Melt extrusion based dosage forms: Excipients and processing conditions for pharmaceutical formulations. J. melt extrusion 2004;97:85-95.   
21.Bamba J, Cave G, Bensouda Y, Tchoreloff P, Pulsieux F, Couarrraze G. Cryoprotection of emulsions in freeze drying: Freezing process analysis. Drug Dev Ind Pharm 1995;21:1749-60.
22.Christensen KL, Pedersen GP, Kristensen HG. Technical optimization of redispersible dry emulsions. Int J Pharm 2001;212:195-202.   [PUBMED]
23.Hansen T, Holm P, Schultz K. Process characteristics and compaction of spraydriedemulsions
containing a drug dissolved in lipid. Int J Pharm 2004;287:55-66.  [PUBMED]
24.Jang DJ, Jeong EJ, Lee HM, Kim BC, Lim SJ, Kim CK. Improvement of bioavailability and photostability of amlodipine using redispersible dry emulsion. Eur J Pharm Sci 2006;28:405-11.[PUBMED]

NOW YOU CAN ALSO PUBLISH YOUR ARTICLE ONLINE.

SUBMIT YOUR ARTICLE/PROJECT AT articles@pharmatutor.org

Subscribe to Pharmatutor Alerts by Email

FIND OUT MORE ARTICLES AT OUR DATABASE