INTRODUCTION:
Drugs are been administered from various routes for delivery
to the systemic circulation. Numerous routes such as oral, nasal, rectal, topical,
parenteral, etc. Among this oral route is considered as the safer route for administration
as it is painless, self-administered, low cost.[1] Nowadays, nearly about
56% of drug comes under Class II and III as per BCS classification that has low
solubility high permeability and low solubility low permeability, remained 34% are
BCS classification Class I drugs have high solubility and high permeability. As
BCS Class II and IV drug have very low solubility that result to low in low bioavailability.
To overcome this problem various new strategies are designed. [2,3]
One
of the advanced formulations is SEDDS, anisotropic mixture of drug, lipid, and surfactant
which consists of one or more hydrophilic cosolvent or co-emulsifier with droplets
size ranging from few Nanometres to several Microns. It can be categorized into
Self Nano-Emulsifying Agent (SNEDDS) and Self Micro-Emulsifying Agent (SMEDDS) with
a range between 100-250 nm and later less than 100 nm.[4]
Lipid-based
formulation amplifies the solubility of the drug during GI transit and fabricates
the lipophilic ambiance at the micro level to allow drug transportation towards
intestinal absorption site.[5] Oral administration for the very first
time in 2000 Pouton reported the SEDDS to delivery of poorly water-soluble drugs
using Miglyol 812 and Tween 85 to enhance both solubility and bioavailability.[6]
Both hydrophilic and hydrophobic drugs can be incorporated within oil surfactant
mixture encapsulated in a single unit dosage form. The drug Moiety Release in the
form of fine emulsion in the gastrointestinal tract lumen. It avoids absorption
by lymphatic system and bypassing hepatic first-pass metabolism. BCS Class II and
Class IV are expected candidates for SEDDS.[7] According to Pouton, lipid
base formulation is classified into four categories.[8]
Fig
1. Classification of SEDDS
Mechanism:
Self-emulsification
occurs due to entropy change that favors in dispersion that is more than the energy
required to increase the surface area of dispersion and negative free energy (ΔԌ)[9].
The free energy of conventional emulsion is a direct function of energy required
to create a new surface between the two-phase. This can be illustrated by-
(ΔԌ)
= ƩNπ
σ
ΔԌ
= Free energy associated with process
N =
Number of droplets
σ
=Interfacial energy
r =
Radius of droplet
For
spontaneous emulsion, very low energy required to for the emulsion, this energy
either can be positive or negative and the interfacial structure must have no resistance
to surface shearing.[9]In due course of time, two-phase of emulsion will
tend to separate to reduce interfacial area and subsequently the free energy of
the system. Conventional emulsifying agent forms a monolayer around the droplet
to stabilize the emulsion, resulting from aqueous dilution hence reduce interfacial
tension and preventing coalescence.[10]
Phase
diagram:
Pseudo
tertiary phase diagram is an authenticated way to construct lipidbased drug delivery
system such as SEDDS. It demonstrates the self-dispersing ability of SEDDS as a
thermodynamically stable self. Nano microcarrier to deliver in the GI lumen, providing
knowledge on phase behavior concerning different formulation aspects. Phase diagram
is constructed to optimize the quantities of different compounds employed in the
preparation of SEDDS.[11]
The
optimized Surfactant is dissolved in the oil phase in different proportion in a
glass test tube than each phase of surfactant and oil phase is titrated against
aqueous phase, turbidity in test tube referred to as Endpoint. Whereas in the dilution
method different ratios of surfactant, co-surfactant, and oil as per requirement
are incorporated for preparing tertiary mixture. Nanoemulsion is evaluated by diluting
the tertiary mixture with a suitable volume of distilled water. The phase diagram
determines the area of nanoemulsion and globule size.[12]
Excipients
Drug
Drug
hydrophilicity/lipophilicity plays a major role in SEDDS formulation. Drug should
have log P ≥ 2. A low dose of the drug is formulated and it should not undergo
first-pass metabolism extensively.[13]
Oil:
Oil
plays a chief role in solubilizing lipophilic drug. Both long and medium-chain triglyceride
oil with various degrees of saturation can be used for the formulation of SEDDS
oil to enhance the ability of drug for efficient absorption in GIT through the intestinal
lymphatic system. Solubility capacity of low hydrophobic drug can be overcome by
bending triglycerides with mono-glycerides and di-glycerides.[14]
Surfactant:
Generally,
non-ionic surfactants that have relatively high hydrophilic-lipophilic balance (HLB)
are suitable for the formulation of SEDDS. Mostly ethorylated poly glycolized glyceride
and polyoxyethelene 20 oleate are used as excipients. Natural emulsifying agents
are quite safer than the synthetic one. Surfactant create interfacial film and reduces
the interfacial tension. Some non-ionic surfactants have lesser degree of toxicitythan
ionic surfactant but may cause moderate reversible change in intestinal wall permeability.
Generally, 30-60% w/w of formulation of surfactant yield better self-emulsificant
in GIT large concentration of surfactant may irritate the GIT wall.[15]
Cosurfactant:
Organic
solvents that are suitable for oral administration assist to dissolve a large amount
of either the hydrophilic surfactant of the drug in the lipid base. This plays the
role of co-surfactant in the microemulsion system to remove interfacial tension
to an even smaller transient negative value. Provides flexibility to achieve different
curvature for the formulation of different concentration of microemulsion.[16]
FIG
2. Diagrammatic representation of SEDDS, SMEDDS and SNEDDS
Formulation:
FIG
3. Classification of formulation process
High
Energy Emulsification Method
1.
High pressure homogenization
(HPH):
High-pressure
homogenisation is needed for nanoemulsion preparation. High-pressure homogenizer
is used to produce extremely low particle size up to 1 nm. The dispersion of two
phases forces the mixture by means of a small inlet orifice at very high pressure
of around500 to 5000 psi.
2.
Ultrasonication:
Another
very efficient method for reducing a droplet size is ultrasonication. Sonicator
probe (sonotrodes) are used to provide high energy. Electric voltage can be changed
due to the expand and contract nature of sonotrods as it contains piezoelectric
quartz crystal. Mechanical vibration is produced when the tip of sonicator touches
liquid medium which results in cavitation. Thus, ultrasound can directly produce
nanoemulsion with droplet size as low as 0.2 mm.
3.
Microfluidization:
Microfluidization
is one of the patented mixing technologies, by using a device called as microfluidizer.
This device was used in a high-pressure positive displacement pump (500- 20000psi),
which forces the product through the interaction chamber, resulting in very fine
particles in the submicron range. This process is repeated many times to obtain
a desired size to produced homogeneous nanoemulsion system.
Low
Energy Emulsification:
1.
Phase inversion emulsification method:
This method involves phase transitions
by applying higher temperatures to the pathway for emulsification.
2.
Spontaneous emulsification:
Nanoemulsion
is spontaneously formed by this method. Preparation of homogeneous and uniform organic
solution consisting of oil and surfactant in water miscible surfactant and hydrophilic
surfactant phase. To form stable o/w emulsion under continuous magnetic stirring
organic phase was injected in aq phase. under reduced pressure aqueous phase was
evaporated.
Application:
Antiretroviral:
AtazanvirBisulfate
(ATV):
Atazanvir
is an Antiretroviral drug for the cure of retrovirus, Human Immunodeficiency Virus
(HIV). The main aim is to keep the HIV in the body at a low level. Many Anti retroviral
drugs go under first pass metabolism and GI degradation, resulting in low bioavailability.
This is overcome by preparing Atazanvir SMEDDS. This drug is an Azapeptid HIV 1
Protease inhibitor which inhibits the Gag-pol protein in HIV 1 infection cells,
resulting in the prevention of mature virion and infection of other cells. Triacetion,
Span20, transcutolHp are used as oil, surfactant and cosurfactant respectively for
drug delivery in ratio 25:50:29% w/w for formation of L-SMEDDS. Further, it was
converted into S-SMEDDS by using Aerosil 200 as solid carrier, resultant particle
size was 65.8 nm with Zita potential-9.2 MV which is stable over 6 months. [19]
Saquinavir
(SQV)
Saquinavir
is an active anti HIV drug under the category of protease inhibitor, It is use as
Regimen for highly active antiretroviral therapy (HAART) Campul MCM, Cremophase
EL and labraft is chosen as oil, surfactant, and co-surfactant repectively for the
formulation of Saquinavir-SMEDDS. Saquinavir was more soluble in capmul (110mg +
4mg/110mg-4mg) then maisine (95mg+3mg/95-3mg) and labrafac (87mg+5mg/87mg-5mg).
The result of this study indicates a maximum up to 98.57% release at time of 45min
from formulation. The average droplet size found to be 92μm without any precipitation.[20]
Diabetes:
Nateglinide:
Nateglinide
is a poorly soluble drug under BCS Class II which is prescribed in DM type II, It
blocks K+ ATP channel hat control Glycemic condition in Type II diabetes. Vasant,
Survarna prepared SEDDS of nateglinide to increase solubility and dissociation rate,
further they converted liquid SEDDS into solid formerly by absorbing into absorbent
aerosil 200. Carpyrol 90 was selected as oil as it shows high solubility to the
drug. SEDDS was prepared by Vortex Method using different concentration of oil,
surfactant and co-surfactant containing 60mg Nateglinide and average globule size
found to be 141.5-240.9nm and drug content was between 92-99.17%. Significant increase
in bioavailability was observed by S-SMEDDS formulation of Nateglinide.[21]
Repaglinide
Repaglinide
remains a drug of choice for diabetic patients with impaired kidney function. Repaglinide
excreted mainly in the bile.S-SNEDDS of Repaglinide have been prepared for improving
the bioavailability of drug and sustain its glucose-lowering action. Four types
of oils have been used for the preparation of SNEDDS (Oleic acid, Isopropyl Myristate
IPM, labrafil 1944 and 2125) with surfactants (Chromophore E135, ChomophoreRH40,
Labrasol and Span 20) and various co-surfactants (Propylene glycol, Lour glycol
FCE). From phase study nanoemulsion existence areas were obtained with oil to surfactant
and co-surfactants ratio were obtained more for IPM compare to other oils. The smallest
average droplet size was 13.51nm and highest average size was 19.68nm. SNEDDS of
Repaglinide in-vitro release profile compare to marketed product.[22]
Anti-hypertensive:
Olmesartanmedoxomil
(olm):
OlmesartanMedoxomil
is an antihypertensive drug under the category of Angiotensin II receptor blocker
with absolute bioavailability less than 26%. Shailesh T Prajapat, Harsh A Joshi
reported OLM-SMEDDS formulation which has a high dissolution rate compare to plain
OLMsuspension. Here 34% Acrysol EL, Transculto P (oil, surfactant) with 20mg of
drug for preparation of SMEDDS. And almost two-fold increase in bioavailability
was observed.[23]
Ramipril
Ramipril
is another ideal drug in case of hypertension with low solubility and bioavailability
around 28-30%. It is an effective inhibitor of angiotensin converting enzymes (ACE)
that prevent conversion of AT I to AT-II. The water titration method was used for
determination solubility of Ramipril and found to be more in orange oil 85.23+2.26/85.23-2.26
compare to other oils, for optimization of formulation Tween 80 and propylene glycol
was used. Best emulsion was found in ratio 2:1 from electrical conductivity (0.283us/cm)
and staining test the formulation was concluded as O/W type microemulsion with viscosity
3.52Cps and conforms that microemulsion formulaic can be used alternative to conventional
dosage form of Ramipril for fine prove bioavailability.[24]
Candesartan cilexetsl:
Condestrancilexetsl
is an esterified prodrug of candesartan used for the treatment of hypertension.
It is the Nano peptide angiotensin II type, receptor antagonist. condestran has
oral bioavailability around 15% so lipid-based formulation is curved out to increase
drug solubility hence bioavailability. The solubility of condestran was high in
capryol 90 (80.12 +_1.04) compare to other oils, formulation prepared usingcapryol90-oil,
labrasol- surfactant and captex 500, caurpul MCM-cosurfactant this passes thermodynamic
stress test with mean globule size 9.5 nm. Viscosity 0.8824 cp. In vitro drug release
study for candesartan cilexetil SMEDDS was extremely significant (p<0.05) as
compared to marketed product.[25]
Anti-emetic
by nasal route
Dimenhydrinate
Nasal
Route has increasingly investigatory for systemic delivery of drugs due to its large
surface area 190cm², High permeation and avoid hepatic first pass metabolism. In
case of nausea and vomiting treatment if the oral route is complicated or not feasible
than nasal administration is unsuitable. Dimenhydrinate belongs to a class of anti-emetic
drug. It is poorly water-soluble. The study aimed to prepare SEDDS for nasal administration
of Dimenhydrinate using diffusion to facilitate permeability through bovine nasal
mucosal tissue was cheated using diffusion chamber (Hugo Sachs Eleckronik Harvard
Apparatus GM6H). Dimenhydrinate show high solubility in Transcutol HP then Campul
MCM and Campule PG8. The tertiary phase was constructed using oil, Cermophor E1
and Labrasolwas surfactant and PEG200-PEG400 was co-surfactant. Dimethyl was loaded
in SEDDS pre-concentrates to 7.5% (w/v). This result in droplet size of 60-220nm
and enhancement in permeability was up to 2-8 fold compared to pure drug.[26]
Anti-hyperuricemic:
6-shogaol:
6-shogaol
is an alkyl phenol compound purified and obtained from the root of ginger. It has
poor aq solubility that results in low bioavailability. SMEDDS of 6-shogaol was
designed by pseudo-ternary phase diagram and central composite design using 18.62%
w/w ethyl oleate (oil phase) and tween 80 (surfactant) to PEG 400 as co-surfactant
in ratio of (1:73:1, w/w). The mean droplet size of resultant spherical shaped homogeneous
droplet was 20.00±0.26nm with 0.18±0.2 poly dispersity. 571.18% enhancement in oral
bioavailability of the drug was observed from the animal study in hyperuricemic
rats. A significant decrease in uric acid volumeand xanthine oxidase activity was
observed by 6-shogaol-SEDDS.[27]
Peptide
delivery:
Polymyxin
B (PMB)
Polymyxin
B is a peptide drug with hydrophilic character, due to the formation of imine conjugation
between the primary amino group of PMB and carboxyl group of cinnamaldehyde it can’t
be incorporated in lipophilic nanocarrier system for oral administration of the
drug. To prepare SEDDS of polymyxin, PMB-cinnamaldehyde conjugation was formed by
covalent bonding between electrophilic carbonyl group of cinnamaldehyde and neucleophillicNH2group
of PMB after nitrogen deprotonation N-H bond pushes the oxygen away from the carbon.
Imine bond is formed due to substitution of oxygen atom. Bovine serum albumin use
to confirm reversibility of imine bond. PMB-cinnamaldehyde shows high solubility
in transcutol, propylene glycol. tween 20, cremophor EL. Four different formulation
was prepared using capmul MCM and peceol- oil phase, cremophore EL and tween 20-surfactant,
and propylenglycol and transcutol as co-surfactant. SEDDS were loaded with PMB-cinnamaldehyde
in concentration of 3.6% with log D value 3.4. 87.1% of primary amine forms imines
with cinnamaldehyde. The mean droplet size of the resultant SEDDS was 199.2±3.3
to 214±1.1 nm.[28]
Flavonoids
Curcumin
Curcumin
is a broad-spectrum antimicrobial, anti parasitic. Due to this Curcumin is an ideal
candidate for chemotherapy of cutaneous Leishmaniasis (CL) with the potential t
o inhibit or kill two different pathogens. Cu-SEDDS was prepared using captox 300(medium-chain
ester), cremophor EL and cremopher RH 40(non-ionic surfactant). total 7 formulation
was prepared using different quantity of oil, surfactant, co-surfactant. The average
size range was from 32.4 to 80.0nm, with negative zeta potential from -1.56to -4.8.
Anti Leishmania activity of cu-SEDDS formulation in terms of IC50 against Leishmaniatropica
range from 0.19 up to 0.37ųg/ml. Hemolysis caused by the formulation of Cu-SEDDS
was 1-2%. This Cu-SEDDS provide effective therapy in low dose compared to unmodified
Curcumin.[29]
Cardiovascular:
Rosuvastatin calcium (ros)
Rosuvastatin calcium is a synthetic lipid-lowering agent,
a reductase used for the treatment of mixed dyslipidemia, primary hypercholesterolemia,
and hypertrigglyceridemia. Ros is very less soluble in aq. Medium with 20% Absolute
bioavailability. Ros shows high solubility in campuol MCM and for satisfactory study
propylene glycol as co-surfactant and cremophor ELP as surfactant was selected.
Ros SEDDS containing oil phase 20 %, surfactant 53.33% and cosurfactant 26.66% was
formulated. This micro emulsion was negatively charged with small particle size
(10.59nm) nerosil200 was used as absorbent for preparation of solid SEDDS. This
S-SEDDS increase solubility and bioavailability of rosuvastatin.[30]
Simvastatin
simvastatin
is a low water soluble drug. The study was conducted by preparing SEDDS with moringaoleifera
and beniseed oils, tween 80 and polyethylene glycol. The MSO and BSO showed good
solubility of the drug as there was no precipitation of the drug. PEG also showed
good solubility as there was no precipitation then liquid SEDDS were formulated.
Prepared formulation was characterized based on self emulsification ability, emulsification
time, phase separation, spontaneity of formation, viscosity. A total of 8 samples
were prepared comprising samples F1-F8 (tween 80, BSO, MSO and PEG-200). F1-F3 formed
clear transparent and stable mixtures and were selected. The mixture that showed
otherwise were rejected. Prepared SEDDS with simvastatin were made to undergo thermal
stability tests that comprise heating cooling cycle, centrifugation test, and freeze-thawing
test and were all found to be stable at different temperature conditions. Percentage
drug content showed good result as most of the formulations showed good drug content
of 70% and above. Cloud point determination of the formulation showed that the formulations
are stable at physiological temperature. This study shows that the formulation will
help to enhance solubility, bioavailability, and fast drug release and therefore
can be suitable for oral delivery systems.[31]
CONCLUSION:
Though
SEDDS have some biopharmaceutical issues such as drug use for formulation, risk
of precipitation, surfactant and its compatibility, effect of oil droplet size whereas
optimization of formulation depends on various factor such as dose encapsulation
efficiency, adequate solvent capacity to dissolve the drug and fate of drug after
its absorption from intestinal mucosa. drug with log P value within 2 is more selectable
candidate for formulation of SEDDS. Fine droplet size of micro emulsion showed a
better Absorption rate than the larger droplet size with the ideal range of 250nm.
Significant change bioavailability is observed between particle size 100nm to 250
nm but still more evidence needs to be collected to prove.[32] Risk of
precipitation involved with no of polymer, surfactant, and triglycerides but there
is no established method available to determine the risk of precipitation. Excessive
use of co-solvent, polymers, co-polymers, and other excipients can affect the supersaturation
process in the self-emulsification of drug.[33] L-SEDDS can be converted
into S-SEDDS by incorporating various adsorbent to enhance its stability. No doubt
that SEDDS has been successfully used to increase drug solubility as well as its
bioavailability of poorly soluble drugs candidates, this approach established to
improve the absorption and therapeutic efficacy of drug. Now a days it is widely
used for targeted drug delivery of anti-cancer, anti-bacterial, anti-viral, anti-hypertensive
drugs. Delivery of natural products such as flavonoids, alkaloids, natural oils
is possible through SEDDS. Overall SEDDS formulation considered as safe and patient
compliance and moreover effective for the delivery of drugs. In conclusion, we should
pay attention to the characteristic analysis of SEDDS and further research and development
should be done on bioavailability studies and mechanical action of different formulation.
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