Self-nano Emulsifying Drug Delivery System (SNEDDS): Future Aspects

Ms. Hiral A. Makadia*, Ms. Ami Y. Bhatt, Mr. Ramesh B. Parmar, Ms. Jalpa S. Paun, Dr. H.M. Tank

Department of pharmaceutics, S.J. Thakkar Pharmacy College, Kalawad Road, Rajkot-360005. Gujarat, India.

*Corresponding Author E-mail: hiralmakadia1612@gmail.com

ABSTRACT:

Oral route is the easiest and most convenient route for drug administration. more than 40% of new chemical entities exhibit poor aqueous solubility, resulting in unsatisfactory oral drug delivery. The major problem in oral drug formulation is low erratic bioavailability. This may lead to high inter and intra variability lack of dose proportionality and therapeutic failure. For improvement of bioavailability of drug is one of the greatest challenges in drug formulation. Various technological strategies are reported in literature including solid dispersions, cyclodextrines complex formation or micronization and different technologies of drug delivery system. SNEDDS may be a promising strategy to improve the rate and extent of oral absorption. SNEDDS are mixture of oil, surfactant, solvents and cosolvents / surfactants. The principle characteristic of these systems in their ability to form oil-in-water (o/w) emulsion or micro emulsion upon mild agitation following dilution by an aqueous phase. The characterization of SNEDDS and application of SNEDDS is also introduced, with particular emphasis being placed on the developments of dosage form of SNEDDS.

KEYWORDS: Self-nano emulsifying drug delivery system, solubility, improvement of bioavailability, surfactant.

INTRODUCTION:

In recent years, the formulation of poorly soluble compounds presented interesting challenges for formulation scientists in the pharmaceutical industry. Up to 40% of new chemical entities discovered by the pharmaceutical industry are poorly soluble or lipophilic compounds, which lead to poor oral bioavailability, high intra and inter subject variability and lack of dose proportionality.^[1] Efforts are ongoing to enhance the oral bioavailability of lipophilic drugs in order to increase their clinical efficacy.^[2] Self emulsifying drug delivery systems have been shown to be successful in improving the oral bioavailability of poorly water soluble and lipophilic drugs.^[3]

Self emulsifying drug delivery systems (SEDDS) also called as self emulsifying oil formulation which are mixtures of oils and surfactants, ideally isotropic, and sometimes containing co-solvants, which emulsify spontaneously to produce fine oil in water emulsion when introduced into aqueous phase under gentle agitation.^[4],[5]Self-nanoemulsifying (SNEDDS), self-microemulsifying (SMEDDS) and self-emulsifying drug delivery systems (SEDDS) to improve the oral bioavailability of poorly water-soluble drugs.^[6-8]

SELF EMULSIFYING THERAPEUTIC SYSTEM

Self-nano emulsifying drug delivery system(SNEDDS) are isotropic mixtures of oil, surfactant, co-surfactant and drug that form fine oil-in-water nanoemulsion when introduced into aqueous phases under gentle agitation. SNEDDS spread readily in the gastrointestinal tract, and the digestive motility of the stomach and the intestine provide the agitation necessary for self-emulsification.^[9]

Mechanism of self emulsification

According to Reiss, Self‐emulsification occurs when the entropy change that favours dispersion is greater than the energy required to increase the surface area of the dispersion. The free energy of the conventional emulsion is a direct function of the energy required to create a new surface between the oil and water phases and can be described by the

DG= S N p r 2s …………. (Equation 1)

Where,

DG = free energy associated with the process,

N = number of droplets,

r = radius of droplets,

s = interfacial energy.

The two phases of emulsion tend to separate with time to reduce the interfacial area and subsequently, the emulsion is stabilized by emulsifying agents, which form a monolayer of emulsion droplets and hence reduce the interfacial energy as well as providing a barrier to prevent coalescence. The specificity of surfactant combination required to allow spontaneous emulsification may be associated with a minimization of the phase inversion temperature, thereby increasing the ease of emulsion.^[10]

Advantages of SNEDDS

 Protection of sensitive drug substances.

 Selective targeting of drug(s) toward specific absorption window in GIT.

 Enhanced oral bioavailability enabling reduction in dose.

 High drug payloads.

 It can be easily stored since it belongs to a thermodynamics stable system.

 Fine oil droplets would pass rapidly and promote wide distribution of the drug throughout the GIT, thereby minimizing the irritation frequently encountered during extended contact between bulk drug substance and the gut wall.

 As compared with oily solutions they provide a large interfacial area for partitioning of the drug between oil and water.^[11-13]

Disadvantages of SNEDDS

 Lack of good predicative in vitro models for assessment of the formulations because traditional dissolution methods do not work, because these formulations potentially are dependent on digestion prior to release of the drug.

 To mimic this, an in vitro model simulating the digestive processes of the duodenum has been developed.

 Need of different prototype lipid based formulations to be developed and tested in vivo in a suitable animal model.^[14],[15]

Factors affecting SNEDDS

 Drugs which are administered at very high dose are not suitable for SNEDDS, unless they exhibit extremely good solubility in at least one of the components of SNEDDS, preferably lipophillic phase. The drugs exhibit limited solubility in water and lipids are most difficult to deliver by SNEDDS.

 The ability of SNEDDS to maintain the drug in solubilized form is greatly influenced by the solubility of the drug in oily phase. If the surfactant or co-surfactant is contributing to a greater extent for drug solubilization, then there could be a risk of precipitation, as dilution of SNEDDS will lead to lowering of solvent capacity of surfactant or co-surfactant.^[16]

Characterization of solid SNEDDS

As the final dosage form of the solid SNEDDS is a tablet or a capsule, the powder properties of the solid emulsion particles are important. The nature and the quantity of liquid SNEDDS adsorbed on the surface of a particular excipient would influence the properties of the obtained solid particles. The ratio of liquid:adsorbent quantity is important. Powder properties, such as density, angle of repose, flow, compressibility index and particle size distribution, are important for processing into dosage form. The globule size of spontaneously formed nanoemulsion would govern its performance in vivo. The desorption of SNEDDS from the surface of the solid particles and its conversion into nanoemulsion is the rate-limiting step for the dissolution and absorption of the drug. In our study, an increase in the globule size of the nanoemulsions was observed when the solid nanoemulsifying particles were dispersed in water. Increase in size was not only related to the carrier used but also to the composition of SNEDDS and properties of the drug. It is necessary to carry out physical characterization of the solid SNEDDS using x-ray diffraction spectroscopy, differential scanning calorimetry and scanning electron microscopy to ensure there is no drug precipitation during preparation of solid SNEDDS. The absence of characteristic drug melting endotherm in differential scanning calorimetry suggests that the drug is in a solubilized state in solid SNEDDS. X-ray diffraction is a useful technique employed in the characterization of crystalline materials. The formation of a diffuse diffraction pattern and the disappearance of characteristic drug peaks indicate that the drug is in a solubilized state in solid SNEDDS. Scanning electron microscopy is useful to investigate the surface properties of the particles and their physical form.^[17]

Formulation considerations and potential components

Successful formulation of SNEDDS depends on the through understanding of the spontaneous nano emulsification process and also on the physicochemical and biological properties of the components used for the fabrication of SNEDDS. The factors influencing the phenomenon of self-nano emulsification are:

 The physicochemical nature and concentration of oily phase, surfactant and co-emulsifier or co surfactant or solubilizer (if included);

 The ratio of the components, especially oil-to-surfactant ratio;

 The temperature and pH of the aqueous phase where nanoemulsification would occur;

 Physicochemical properties of the drug, such as hydrophilicity/lipophilicity, pKa and polarity.

These factors should receive attention while formulating SNEDDS. In addition, the acceptability of the SNEDDS components for the desired route of administration is also very important while formulating SNEDDS.^[18]

Components of SNEDDS

Oil Phase

The oil phase has great importance in the formulation of SNEDDS as physicochemical properties of oil (e.g., molecular volume, polarity and viscosity) significantly govern the spontaneity of the nanoemulsification process, droplet size of the nanoemulsion, drug solubility.^[19-21]Usually, the oil, which has maximum solubilizing potential for the selected drug candidate, is selected as an oily phase for the formulation of SNEDDS. The selected oil should be able to yield nanoemulsions with small droplet size.

Table 1: Commonly used oily phases^[25],[26]

General class	Examples	Commercial name
Medium chain triglyceride	Triglycerides of capric/caprylic acids	Miglyol 810, 812, Labrafac CC Crodamol GTCC, Captex 300, 355
	Triacetin	Captex 500
Medium-chain mono- and di-glycerides	Mono- and di-glycerides of capric/caprylic acids	Capmul MCM, Imwitor 742, Akoline MCM
Long-chain mono-glycerides	Glyceryl monooleate	Peceol, Capmul-GMO
Propylene fatty acid esters	PG monocaprylate	Capryol 90, Capmul PG-8, Sefsol 218
	PG monolaurate/dilaurate	Lauroglycol 90, Capmul PG-12, Lauroglycol FCC
	PG dicaprylate/caprate	Miglyol 840, Captex 200
Fatty acid esters	Ethyl oleate	Crodamol EO

Hence, the choice of the oily phase is often a compromise between its ability to solubilize the drug and its ability to facilitate formation of nanoemulsion with desired characteristics.^[22] The lipophilicity of the oil and concentration of oily phase in SNEDDS are directly proportional to the nanoemulsion size. Hence, it may be difficult for a single oily component to have optimum properties with respect to nanoemulsification and drug delivery. In certain cases, using a mixture of oils can also be used to meet optimum properties of the oily phase. A similar concept has been utilized for nanoemulsions and microemulsions.^[23],[24]

Surfactants

The choice of surfactant is also critical for the formulation of SNEDDS. The properties of the surfactant, such as HLB (in oil), viscosity and affinity for the oily phase, have great influence on the nanoemulsification process, self-nanoemulsification region and the droplet size of nanoemulsion. The concentration of the surfactant in the SNEDDS has considerable influence on the droplet size of nanoemulsions.^[27-29] The acceptability of the selected surfactant for the desired route of administration and its regulatory status (e.g., generally regarded as safe) must also be considered during surfactant selection. Many nonionic surfactants, such as Cremophor EL (polyethylene glycol [PEG]-35-castor oil), have the ability to enhance permeability and uptake of drugs that are susceptible to P-glycoprotein-mediated efflux.^[30-32] However, these surfactants can also have structure-dependent, concentration-dependent and route of administration-dependent adverse effects. Cremophor EL can cause anaphylactic shock and histamine release on parenteral administration, Certain surfactants might cause irritation to the GI mucosa and skin at higher concentrations. A variety of surfactants are available for formulation of SNEDDS, which can be used either alone or in combination to obtain SNEDDS yielding nanoemulsions with desirable characteristics while avoiding or minimizing unfavorable effects offered by surfactants.^[33]

Table 2: Commonly used surfactants ^[26][34]

General class	Examples	Commercial name
Polysorbates	Polyoxyethylene-20-sorbitan monooleate	Tween® 80, Crillet 4
	Polyoxyethylene-20-sorbitan monolaurate	Tween 20, Crillet 1
Sorbitan esters	Sorbitan monooleate	Span® 80, Crill 4
	Sorbitan monolaurate	Span 20, Crill 1
	Sorbitan monostearate	Span 60, Crill 3
Polyoxyethylene castor oil	Polyoxyethylene-35-castor oil	Cremphor® EL, Etocas 35 HV
Polyoxyethylene hydrogenated castor oil	Polyoxyethylene-40-hydrogenated castor oil	Cremophor RH 40, HCO-40, Croduret™ 40 LD
	Polyoxyethylene-60-hydrogenated castor oil	Cremophor RH 60, HCO-60
Polyoxyethylene-stearate	Polyethylene glycol-660-12-hydroxystearate	Solutol HS 15®
Polyoxyethylene-vitamin E	Tocopheryl Polyethylene glycol 1000-succinate	Vitamin E TPGS
Sucrose esters	Sucrose laurate	-----------
	Sucrose palmitate	-----------
Polyglycolyzed glycerides	Linoleoyl macrogol glycerides	Labrafil® 2125 CS
	Oleoyl macrogol glycerides	Labrafil 1944 CS
	Polyglyceryl oleate	Plurol® oleique CC 497
	Lauroyl macrogol glycerides	Gelucire® 44/14
	Stearoyl macrogol glycerides	Gelucire 50/13

Co-emulsifiers, Co-surfactants or Solubilizers

Coemulsifiers, cosurfactants or solubilizers are typically employed in the SNEDDS for pharmaceutical use. They can be incorporated in SNEDDS for different purposes, including:

 To increase the drug loading to SNEDDS;

 To modulate self-nanoemulsification time of the SNEDDS;

 To modulate droplet size of nanoemulsion.

Surfactants hydrophilic or lipophilic and/or amphiphilic solubilizers with pharmaceutical acceptability are used for this purpose. Amphiphilic solubilizers, such as propylene glycol, PEG and glycol ethers (diethylene glycol monoethyl ether or Transcutol® P), are often used in the SNEDDS to improve drug loading and time required for self-nano emulsification..^{[27],[29],[34],[35]}

Table 3: List of commonly used solubilizers.^[26,][36]

General class	Examples
Short-chain alcohols	Ethanol, benzyl alcohol
Alkane diols and triols	Propylene glycol
	Glycerol
Polyethylene glycols	Polyethylene glycol 400
Glycol ethers	Diethylene glycol monoethyl ether (Transcutol®)

Aqueous Phase

The droplet size and stability of nanoemulsion is influenced by the nature of aqueous phase where SNEDDS would be introduced. Hence, pH and ionic content of aqueous phase should be given due importance while designing SNEDDS. It is well known that electrolytes can have influence on the nanoemulsion characteristics, such as droplet size and physical stability.^[37] Hence, it is advisable to evaluate the self-nanoemulsification of the SNEDDS and the characteristics of the resultant nanoemulsion in aqueous phases with varying pH and/or electrolyte concentration (depending upon the type of application). In addition to plain water, Ringer's solution, simulated gastric fluid (pH 1.2), simulated intestinal fluid (pH 6.8) and phosphate buffered saline can be used as aqueous phase to evaluate spontaneous nanoemulsification of SNEDDS.^[27]

Techniques of self-emulsifying nanoparticle development

Selfemulsifying nanoparticle

Nanoparticle technology can be applied to the formulation of self emulsifying nanoparticle. One of the solvent was injection, in this method the prepared molten lipid mass contained lipid, surfactant and drug. This lipid molten mass was injected drop wise into a non solvent system. This is filtered and dried to get nanoparticles. By this method 100 nm size particle with 70‐75% drug loading efficiency was obtained.^[38]

Sonication emulsion diffusion evaporation

By this method co‐load 5‐flurouracil and antisense EGFR (epidermal growth factor receptor) plasmids into biodegradable PLGA/O‐CMC nanoparticles. The mixture of PLGA (poly‐lactide‐coglycolide) and O‐CMC (O‐carboxmethyl‐chitosan) had a SE effect, with no additional surfactant required.^[39]

Multiple emulsion solvent evaporation

Trickler et al. developed a novel nanoparticle drug delivery system consisting of chitosan and glyceryl monooleate (GMO) for the delivery of paclitaxel (PTX). These chitosan/ GMO nanoparticles, with bioadhesive properties increased cellular association and was prepared by multiple emulsion (o/w/o) solvent evaporation methods.^[40]

Table 4: Different categories of drugs, formulations and excipients used in self nano emulsifying therapeutic system

Categories	Drug(s)	Formulation type	Excipients (oil,surfactant, Co-surfactant/ cosolvent)	Comments	Refer-ences
Beta-blocker	Carvedilol	SNEDDS Liquisolid tablet	MCT/ Migliol® 812, HCO-40, Transcutol® HP	Modifying silicon dioxide physical form from amorphous into granulated improved the physical properties of both liquisolid powders and tablets.	41
Third generation cephalo-sporin	Cefpodo- xime proxetil (CFP)	SNEDDS NANO-EMULSION	CAE, Cr-EL or SHS 15, Akoline MCM	The potential of Akoline-MCM, to act as a co-surfactant was established in these present investigation. Studies on ternary phase diagrams indicated that CFP and the pH of dilution medium significantly affects the area of the nanoemulsion formation for the selected system.	27
Anti-histamine	Cinnarizine (CNZ)	SNEDDS EMULSION	Oleic acid, Tween-80, Capmul MCM C-8	SNEDDS formed from oleic acid, tween 80 and Capmul MCM C-8 and δ(mix) surfactant co-surfactant ratio (2:1) and δ(mix)-oil ratio (6:1) is a promising approach to improve the solubility, dissolution rate and bioavailability of CNZ.	42
Calcium channel blocker	Felodipine (FLD)	SNEDDS GEL	Miglyol® 840, Cremophor® EL, Capmul® MCM	Gelled SNES containing FLD encased in a hydrophobic GEL coat can serve as an alternative for conventional extended release formulations. Moreover, by varying the contents of release enhancer and gelling agent in such composition, the release profile of FLD can be manipulated as required.	43
Estrogen receptor antagonist	Tamoxifen citrate	SNEDDS EMULSION	Caproyl 90, Cremophor RH40, propylene glycol	SNEDDS of tamoxifen citrate showed a significant increase in release rate compared to the drug suspension under the same conditions.	44
Anti hyper-lipidemic	Probucol	SNEF	Sesame oil, Cremophor RH40, Ethanolactant	The bioavailability from the surfactant solution and the oil solution were slightly lower compared to the sndds	45
Vitamin A	Transretinol acetate	SNEDDS EMULSION	Soyabean oil, Cremophor EL, Capmul MCM-C8	Surfactant to cosurfactant ratio 2:1 produce nanoemulsion have particle size range of 0.03-0.051m	46

Evaluation parameters of SNEDDS

Thermodynamic stability studies

The physical stability of a lipid –based formulation is also crucial to its performance, which can be adversely affected by precipitation of the drug in the excipient matrix. In addition, poor formulation physical stability can lead to phase separation of the excipient, affecting not only formulation performance, but visual appearance as well. In addition, incompatibilities between the formulation and the gelatin capsules shell can lead to brittleness or deformation, delayed disintegration, or incomplete release of drug.

i. Heating cooling cycle: Six cycles between refrigerator temperature (4°C) and 45°C with storage at each temperature of not less than 48 h is studied. Those formulations, which are stable at these temperatures, are subjected to centrifugation test.

ii. Centrifugation: Passed formulations are centrifuged thaw cycles between 21°C and +25°C with storage at each temperature for not less than 48 h is done at 3500 rpm for 30 min. Those formulations that does not show any phase separation are taken for the freeze thaw stress test.

iii. Freeze thaw cycle: Three freeze for the formulations. Those formulations passed this test showed good stability with no phase separation, creaming, or cracking.

Dispersibility test

The efficiency of self-emulsification of oral nano emulsion is assessed using a standard USP XXII dissolution apparatus II. One milliliter of each formulation was added to 500 ml of water at 37 ± 0.5C. A standard stainless steel dissolution paddle rotating at 50 rpm provided gentle agitation. The in vitro performance of the formulations is visually assessed using the following grading system

Grade A: Rapidly forming (within 1 min) nanoemulsion, 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 minutes

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

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 recommend for SNEDDS formulation. ^[47]

Droplet size analysis and Particle size measurements

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. Light scattering is monitored at 25°C at a 90° angle, after external standardization with spherical polystyrene beads. The nanometric size range of the particle is retained even after 100 times dilution with water which proves the system’s compatibility with excess water. ^{[48], [49]}

Zeta potential measurement

This is used to identify the charge of the droplets. In conventional SNEDDSs, the charge on an oil droplet is negative due to presence of free fatty acids.

Refractive index and Percentage Transmittance

Refractive index and percent transmittance proved the transparency of formulation. The refractive index of the system is measured by refractometer by placing drop of solution on slide and it compare with water (1.333). The percent transmittance of the system is measured at particular wavelength using UV-spectrophotometer keeping 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.

In Vitro Diffusion study

In vitro diffusion studies were performed for all the formulations developed, using a dialysis technique. The dialyzing medium was phosphate buffer pH 6.8. One end of pretreated cellulose dialysis tubing (7 cm in length) was tied with thread, and then 1 ml of self nano-emulsifying formulation was placed in it along with 0.5 ml of dialyzing medium. The other end of the tubing was also secured with thread and was allowed to rotate freely in 200 ml of dialyzing medium and stirred continuously at 100 rpm with magnetic bead on magnetic plate at 37°C. Aliquots of 1 ml were removed at different time intervals and diluted further. Volume of aliquots was replaced with fresh dialyzing medium each time. These samples were analyzed quantitatively for drug dialyzed across the membrane at corresponding time by using UV-visible spectrophotometer.

Drug content

Drug from pre-weighed SNEDDS 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.^[50],[51]

CONCLUSION:

SNEDDS is promising approach for BCS class II or IV and drug compounds with poor aqueous solubility. This is the method suited for lipophilic drugs where resulting emulsification gives faster dissolution rates and absorption. The oral delivery of hydrophobic drugs can be made possible by SNEDDS which have been shown to substantially improve oral bioavailability with future development of this technology SNEDDS will continue to enable novel applications in drug delivery and solve problems associated with the delivery of poorly soluble drugs.

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Received on 01.01.2013 Accepted on 30.01.2013

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