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Self Micro-Emulsifying Drug Delivery System (SMEDDS)

DEPARTMENT OF PHARMACEUTICS

R. C. Patel Institute of Pharmaceutical Education & Research; Shirpur.

Dist: Dhule, Maharashtra.

Presented By:

Savale Sagar KishorM. Pharm (1st sem)Date - 3/10/2015

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CONTENT

1. Introduction

2.Defination

3. Types of SMDDS

4. Aim of SMDDS

5. Advantages of SMDDS

6. Disadvantages of SMDDS

7. Composition of SMDDS

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8. Mechanism of SMEDDS

9. Formulation of SMEDDS

10. Evalution of SMEDDS

11. Applications of SMEDDS

12. Conclusion

13. References

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1. In recent years, much attention has been focused on oral dosage forms using a self-micro emulsifying drug delivery system (SMEDDS) for the purpose of improving the solubility and absorption of poorlywater-soluble drugs.

2. SMEDDS consists of a mixture of drugs, oils, surfactants and/or other additives.Gentle mixing of these ingredients in aqueous media generates micro-emulsions with a droplet size in arange of 10-100 nm.

3. SMEDDS has been shown to improve absorption of drugs by rapid self-microemulsification in the stomach, with the micro-emulsion droplets subsequently dispersing in thegastrointestinal tract to reach sites of absorption .

4. resultant small droplet size from SMEDDS provides a large interfacial surface area for drug release and absorption, and the specific components of SMEDDS promote the intestinal lymphatic transport of drugs Oral absorption of several drugs has been enhanced by SMEDDS.

Introduction

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Definition- “SMEDDS are defined as isotropic mixtures of natural or synthetic oils, solid and 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.

Self Micro-Emulsifying Drug Delivery System (SMEDDS)

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The basic difference between self emulsifying drug delivery systems (SEDDS) also called as self emulsifying oil formulation (SEOF)

and

SMEDDS is SEDDS typically produce opaque emulsions with a droplet size between 100 and 300 nm while ,

SMEDDS form transparent micro emulsions with a droplet size of less than 50 nm the concentration of oil in SMEDDS is less than 20 % as compared to 40-80% in SEDDS.

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1.O/W Micro emulsion

2.W/O Micro emulsion

Types of SelfMicroemulsion

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Most of the new drug candidates in development today are sparingly soluble and associated with poor bioavailability

The main purpose is to prepare SMEDDS for “oral bioavailability enhancement of a poorly water soluble drug”.

AIM OF SMEDDS

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Biopharmaceutical Classification System

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according to bio pharmaceutical classification system(BCS) the class II drugs have poor solubility and high permeability , thus the rate limiting process of absorption is the drug dissolution step. Formulation plays the major role in improving the rate and extent of absorption of such drugs from GI tract.

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Advantages of SMEDDS1. Improvement in oral bioavailability

Dissolution rate dependent absorption is a major factor that limits the bioavailability of numerous poorlywater soluble drugs. The ability of SMEDDS to present the drug to GIT in solubilized and micro emulsifiedform (globule size between 1-100 nm) and subsequent increase in specific surface area enable moreefficient drug transport through the intestinal aqueous boundary layer and through the absorptive brushborder membrane leading to improved bioavailability

2.Ease of manufacture and scale-up

Ease of manufacture and scale- up is one of the most important advantages that make SMEDDS uniquewhen compared to other drug delivery systems like solid dispersions, liposomes, nano particles, etc.,dealing with improvement of bio-availability. SMEDDS require very simple and economical manufacturingfacilities like simple mixer with agitator and volumetric liquid filling equipment for large-scalemanufacturing. This explains the interest of industry in the SMEDDS.

3. Reduction in inter-subject and intra-subject variability and food effectsThere are several drugs which show large inter-subject and intra-subject variation in absorption leading todecreased performance of drug and patient non-compliance. Food is a major factor affecting the therapeuticperformance of the drug in the body. SMEDDS are a benefit for such drugs. Several research papersspecifying that, the performance of SMEDDS is independent of food and, SMEDDS offer reproducibilityof plasma profile are available

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4. Ability to deliver peptides that are prone to enzymatic hydrolysis in GITOne distinctive property that makes SMEDDS superior as compared to the other drug delivery systems istheir ability to deliver macromolecules like peptides, hormones, enzyme substrates and inhibitors and theirability to offer protection from enzymatic hydrolysis. The intestinal hydrolysis of pro drug bycholinesterase can be protected if Polysorbate 20 is emulsifier in micro emulsion formulation .Thesesystems are formed spontaneously without aid of energy or heating thus suitable for thermo labile drugs

Advantages of SMEDDS over emulsion

1.SMEDDS not only offer the same advantages of emulsions of facilitating the solubility of hydrophobic drugs, but also overcomes the drawback of the layering of emulsions after sitting for a long time. SMEDDS can be easily stored since it belongs to a thermodynamics stable system.

2. Microemulsions formed by the SMEDDS exhibit good thermodynamics stability and optical transparency. The major difference between the above microemulsions and common emulsions lies in the particle size of droplets. The size of the droplets of common emulsion ranges between 0.2 and 10 μm, and that of the droplets of microemulsion formed by the SMEDDS generally ranges between 2 and 100 nm (such droplets are called droplets of nano particles).Since the particle size is small, the total surface area for absorption and dispersion is significantly larger than that of solid dosage form and it can easily penetrate the gastrointestinal tract and be absorbed. The bioavailability of the drug is therefore improved.

3. SMEDDS offer numerous delivery options like filled hard gelatin capsules or soft gelatin capsules orcan be formulated in to tablets whereas emulsions can only be given as an oral solutions.

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Dis-Advantages of SMEDDS1.One of the obstacles for the development of SMEDDS and other lipid-based formulations is the lack of good predicative in vitro models for 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.

4. 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.

6. 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.

7. The precipitation tendency of the drug on dilution may be higher due to the dilution effect of thehydrophilic solvent.

8. Formulations containing several components become more challenging to validate.

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COMPOSITION OF SMEDDS

Oils

Surfactants

Cosolvents

Cosurfactant

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In order to make SMEDDS systems pharmaceutically acceptable, it is necessary to prepare such systems by using nontoxic and safe components. Oil from natural sources and their derivatives, e.g. triglycerides and fatty acid methyl esters are easily degraded by microorganism and considered to be harmless to the environment. The formation of bicontinuous micro emulsions with mineraloils has been intensively investigated in model experiments and for application in industrial products. An acceptable lipophilic phase for pharmaceutical useswould be vegetable oils. The extension of a microemulsion region generally depends on nature of oil. This is due to differences in oil penetration into thesurfactant layer. Example:Castor oil, Sunflower oil, Olive oil, Seseam oil,Hydrogenated specialty oils

Oil Phase

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Surfactant

A surfactant molecule is formed by two parts with different affinities for the solvents. One of them has affinity for water (polar solvents) and the other has for oil(non-polar solvents). A little quantity of surfactant molecules rests upon the water-air interface and decreases the water surface tension value (the force per unit area needed to make available surface). That is why the surfactant name: “surface active agent”.

Classification –

Surfactant molecules may be classified based on the nature of the hydrophilic group within the molecule. The four main groups of surfactants aredefined as follows,

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1. Anionic surfactants2. Cationic surfactants3. Ampholytic surfactants4. Nonionic surfactants

1. Anionic Surfactants, where the hydrophilic group carries a negative charge such as carboxyl (RCOO-),sulphonate (RSO3-) or sulphate (ROSO3-).Examples: Potassium laurate, sodium lauryl sulphate.

2: Cationic surfactants, where the hydrophilic group carries a positive charge.Example: quaternary ammonium halide.

3: Ampholytic surfactants (also called zwitterionic surfactants) contain both a negative and a positive charge.Example: sulfobetaines.

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4. Nonionic surfactants, where the hydrophilic group carries no charge but derives its water solubility from highly polar groups such as hydroxyl or polyoxyethylene (OCH2CH2O).Examples: Sorbitan esters (Spans), polysorbates (Tweens).

Nonionic surfactants with high hydrophiliclipophilic balance (HLB) values are used in formulation of SMEDDS. The usual surfactant strength ranges between 30-60% w/w of the formulation in order to form a stable SMEDDS.Surfactants having a high HLB and hydrophilicity assist 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 amount of hydrophobic drug compounds6.

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Cosolvents

Organic solvents such as ethanol, propylene glycol (PG) and polyethylene glycol (PEG) aresuitable for oral delivery and they enable the dissolution of large quantities of either the hydrophilic surfactant or the drug in the lipid base. solvents can even act as co surfactants in microemulsion systems. Alternately alcohols and other volatile cosolvents have the disadvantage of evaporating into the shells of the soft gelatin or hard sealed gelatin capsules in conventional SMEDDS leading to drug precipitation.

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For the production 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 reduce the concentration of surfactants. Co-surfactants together with the surfactants provide the sufficient flexibility 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 solubilization of drug in the SMEDDS.

Co-surfactant

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Oil Phase• Isopropyl Myristate• Oleic acid• Olive oil• Mineral oil• Medium chain triglyceride• Soyabean oil• Captex 355• Isopropyl Palmitate• Sunflower oil• Safflower oil

Surfactant• Tween 80• Tween 40• Span 40• Labrafil M1944CS• Polyoxyethylene-35-ricinoleate• Brij 58• CremophorEL• Lecithin

Co-surfactant• Propylene glycol• Ethylene glycol• Ethanol• 1-butanol• Isopropyl alcohol• PEG 600• Glycerol• PEG 400

Examples

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Mechanism

self-emulsification occurs when the entropy change that favors dispersion is greater than the energy required to increase the surface area of the dispersion.

The free energy of a conventional emulsion formation is a direct function of the energy required to create a new surface between the two phases and can be described by equation

Where, G is the free energy associated with the process (ignoring the free energy of mixing), N is the number of droplets of radius, r, and Ợ represents the interfacial energy. With time, the two phases of the emulsion will tend to separate, in order to reduce the interfacial area, and subsequently, the free energy of the systems.

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Formulation of SMEDDS

Drug has to dissolve in to oil phase(lipophilic part) of microemulsion.Water phase is combined with the surfactant and then cosurfactant is added slowly with constant stirring until the system is become transparent.The amount of surfactant and co-surfactant to be added and the parent oil phase that can be incorporated is determined with the help of pseudo ternary phase diagram.Ultrasonicator can finally used to achieve the desired range for the dispersed phase.It is then allow to equilibrate. Gel may be prepared by the addition of the gelling agent to above microemulsion.

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Phase Behaviour

For four or more components pseudo ternary phase

diagrams are used to study the phase behaviour.

In this diagram a corner represent a binary mixture

of two components such as water/drug, oil/drug or

surfactant/co-surfactant.

A quaternary phase diagram is time consuming .

pseudo ternary phase diagram is constructed to

find out the different zones of micro emulsions.

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METHOD OF PREPARATION1. Phase Titration Method2. Phase inversion Method1. Phase Titration Method dilution of an oil-surfactant mixture with water.(w/o)

dilution of a water-surfactant mixture with oil.(o/w)

mixing all components at once. In some systems, the order of ingredient addition may determine whether a

microemulsion forms.

2.Phase inversion method

Phase Inversion Temperature (PIT), i.e., the temperature range in which an o/w microemulsion inverts to a w/o type or vice versa.

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Evaluation Test

1. Thermodynamic Stability Studies2. Dispersibility test3. Turbidimetric Evaluation4. Viscosity Determination5. Droplet Size Analysis and Particle Size Measurements6. Refractive Index and Percent Transmittance7. Electro Conductivity Study8. In vitro Diffusion Study9. Drug Content10. In vivo permeability studies

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1. THERMODYNAMIC STABILITY STUDIESHeating cooling cycle

•Six cycles between refrigerator temperature 4 C and 45 C with storage at each temperature of not less than 48 h is ⁰ ⁰studied.

•Those formulations, which are stable at these temperatures, are subjected to centrifugation test.

Centrifugation

•Passed formulations are centrifuged at room temperature at 3500 rpm for 30 min.

•Those formulations that does not show any phase separation are taken for the freeze thaw stress test.

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Freeze thaw cycle:-

Freeze was employed to evaluate the stability of formulation.

Thermodynamic stability was evaluated at difference temp. To check the effect of temp. the formulation was subjected to freeze thaw cycle(-20ºC) for 2-3 days.

Those formulations passed this test showed good stability with no phase separation, creaming, or cracking.

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2. DISPERSIBILITY TEST:-The efficiency of self-emulsification of oral nano or micro emulsion is evaluated by using a standard USP XXII dissolution apparatus for dispersibility test.

Solution Tested: 1ml

Medium: 500 ml water

Temperature: 37 ± 1 C.⁰Paddle speed : 50 rpm

Grade A: Rapidly forming (within 1 min) nano-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 2 min.

Grade D: Dull, grayish white emulsion having slightly oily appearance that is slow to emulsify (longer than 2 min).

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Grade E: Formulation, exhibiting either poor or minimal emulsification with large oil globules present on the surface.

Grade A and Grade B formulation will remain as nanoemulsion when dispersed in GIT. While formulation falling in Grade C could be recommended for SMEDDS formulation.

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3.TURBIDIMETRIC EVALUATION:-

Nepheloturbidimetric evaluation is done to monitor the growth of emulsification.

Fixed quantity of Self emulsifying system is added to fixed quantity of suitable medium (0.1N hydrochloric acid) under continuous stirring (50 rpm) on magnetic hot plate at appropriate temperature, and the increase in turbidity is measured, by using a turbidimeter.

However, since the time required for complete emulsification is too short, it is not possible to monitor the rate of change of turbidity (rate of emulsification)

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4.VISCOSITY DETERMINATION:- The SMEDDS system is generally administered in soft gelatin or hard gelatin capsules. So, it should be easily

pourable into capsules and such systems should not be too thick.

The rheological properties of the micro emulsion are evaluated by Brookfield viscometer.

The viscosities determination conform whether the system is w/o or o/w.

If the system has low viscosity then it is o/w type of the system If the system has high viscosity then it is w/o type of the system

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5.DROPLET SIZE ANALYSIS:-The droplet size of the emulsions is determined by photon correlation spectroscopy (which analyses the fluctuations in light scattering due to Brownian motion of the particles) using a Zetasizer able to measure sizes between 10 and 5000 nm.

6. REFRACTIVE INDEX AND PERCENT TRANSMITTANCE:-Refractive index and percent transmittance prove the transparency of formulation.

The refractive index of the system is measured by refractometer by putting a drop of solution on slide and comparing it with water (1.333).

The percent transmittance of the system is measured at particular wavelength using UV spectrophotometer by using distilled water as blank.

If refractive index of system is similar to the refractive index of water (1.333) and formulation have percent transmittance > 99 percent, then formulation have transparent nature.

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7.ELECTRO CONDUCTIVITY STUDY:-

The SMEDD system contains ionic or non-ionic surfactant, oil, and water.

This test is performed for measurement of the electro conductive nature of system.

The electro conductivity of resultant system is measured by electro conductometer.

In conventional SEDDSs, the charge on an oil droplet is negative due to presence of free fatty acids.

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8. IN VITRO DIFFUSION STUDY:-In vitro diffusion studies are carried out to study the drug release behavior of formulation from liquid crystalline phase around the droplet using dialysis technique.

9.DRUG CONTENT:-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.

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Applications

SUPERSATURABLE SMEDDS (S-SMEDDS):The high surfactant level typically present in SMEDDS formulation can lead to GI side effects and a new class of supersaturable formulations including supersaturable SMEDDS. (S-SMEDDS) formulations have been designed and developed to reduce the surfactant side effects and achieve rapid absorption of poorly soluble drugs

SOLID SMEDDS: SMEDDS are normally prepared as liquid dosage forms that can be administrated in soft gelatin capsules, which have some disadvantages especially in the manufacturing process. An alternative method is the incorporation of liquid self emulsifying ingredients into a powder in order to create a solid dosage form (tablets, capsules). A pellet formulation of progesterone in SMEDDS has been prepared by the process of extrusion /spheronization to provide a good in vitro drug release (100% within 30 min, T50% at 13 min). The same doseof progesterone (16 mg) in pellets and in the SEDDS liquid formulation resulted in similar AUC, C max andT max values2

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OtherApplications

Parenteral

Administration.

Oral drug delivery.

Topical drug

delivery.

Ocular and

pulmonary

delivery.

Micro-emulsion

s in biotechno

logy

Other Applications

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Marketed Product of SMEDDS

Drug Name Compound Dosage form Company Indication

Neoral® Cyclosporine A/I Soft gelatin capsule Novartis Immune suppressant

Norvir® Ritonavir Sof tgelatin capsule Abbott Laboratories

HIV antiviral

Fortovase® Saquinavir Soft gelatin capsule Hoffmann-La Roche inc. HIV antiviral

Agenerase® Amprenavir Soft gelatin capsule Glaxo Smithkline HIV antiviral

Convulex® Valproic acid Soft gelatin capsule Pharmacia Antiepileptic

Lipirex® Fenofibrate Hard gelatin capsule Genus Antihyper-lipoproteinemic

Sandimmune® Cyclosporine A/II Soft gelatin capsule Novartis Immuno suppressant

Targretin® Bexarotene Soft gelatin capsule Ligand Antineoplastic

Rocaltrol® Calcitriol Soft gelatin capsule Roche Calcium regulator

Gengraf® Cyclosporine A/III Hard gelatin capsule Abbott Laboratories Immuno suppr

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Conclusion

Self-microemulsifying drug delivery system is a novel approach for the formulation of drug compounds with poor aqueous solubility. Self micro emulsifying drug delivery systems (SMEDDS) are mixtures of oils, Cosolvents and surfactants, which is isotropic in nature. When introduced into aqueous phase, it emulsifies spontaneously to produce fine o/w emulsion under gentle agitation. SMEDDS represent a good alternative for the formulation of poorly water soluble drugs. SMEDDS improve the dissolution of the drug due to increased surface area on dispersion and solubility effect of surfactant. The oral delivery of hydrophobic drugs can be made possible by SMEDDSs, which have been shown to substantially improve oral bioavailability. By this approach it is possible to prolong the release of drug via incorporation of polymer in composition. SMEDDS appears to be unique &industrially feasible approach. With future development.

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Reference

1.Spernath A, Aserin A (December 2006). "Microemulsions as carriers for drugs and nutraceuticals".Adv Colloid Interface Sci 128-130: 47–64. doi:10.1016/j.cis.2006.11.016. PMID 17229398.

2.Tang J: Self-Emulsifying Drug Delivery Systems: strategy for improving oral delivery of poorlysoluble drugs. Cur Drug Th 2007; 2: 85-93.

3.Burcham DL, Maurin MB, Hausner EA and Huang SM: Improved oral bioavailability of the hypocholesterolemic DMP 565 in dogs following oral dosing in oil and glycol solutions. Biopharmaceutics & Drug Disposition 1997; 18:737-742. 4. Serajuddin AT, Sheen PC, Mufson D, Bernstein DF and Augustine MA: Effect of vehicle amphiphilicity on the dissolution and bioavailability of a poorly water soluble drug from solid dispersion. Journal of Pharmaceutical Sciences 1988; 77:414-417.

5.Pouton CW: Effects of the inclusion of a model drug on the performance of self-emulsifying formulations. Journal of Pharmacy & Pharmacology 1985; 37:1p.

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