enhancement of bioavability of poorly water soluble drug

1. Department of Pharmaceutics
PATALDHAMAL WADHWANI COLLEGE OF PHARMACY, YAVATMAL-(M.S)445001.
Sant Gadge Baba Amravati University, Amravati.
Maharashtra(India)
(2016-2017)
Presented By:-
SachinS.Rasekar
M.Pharm(III)Sem
Guided by:
Dr. Bharti V. Bakade
M. Pharm, Ph.D.

2. Introduction
Aim And objective
Composition ofSEDDS
Mechanism ofself emulsification
Formulation Approach
Evaluation Test
Conclusion
References

3. Self-emulsifying drug delivery systems (SEDDS )
are defined as isotropic mixtures of oils,
surfactants and co-solvents.
 .
Combination
of all these
makes
SEDDS
oil
surfact
ant
Co-
Surfact
ant
Drug

4. 40% of New Drug Candidates show poor aqueous
solubility and thus poor bioavailability.
BCS Class II DRUGS (Low solubility-High
permeability) – dissolution is rate limiting step for
absorption.
E.g. of BCS Class II Drugs:-
Acetylsalicylic Acid, Ibuprofen, Captopril, ibrutinib,
curcumin etc.

5.  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

6. Quick Onset of Action
Reduction in the Drug Dose
Ease of Manufacture & Scale-up
Improvement in oral bioavailability
Inter-subject and Intra-subject variability and food effects
No influence of lipid digestion process
Increased drug loading capacity
Control of delivery profile
Protection of sensitive drug substance

7. Lack of good in vitro models for assessment of the formulations
for SEDDS.
The traditional dissolution methods does not work, because
these formulations potentially are dependent on digestion prior
to release of the drug.
The large quantity of surfactant in self-emulsifying formulations
(30-60%) irritates
Volatile co-solvents can migrate on capsule shell

8. Excipient in Formulation
Content of Formulation
Type
I
Type
II
Type
IIIA
Type
IIIB
Type
IV
Oils(Triglycerides or mixed mono and
Diglycerides)
100
%
40-
80%
40-
8%
<20
%
Water Insoluble Surfactant (HLB < 12) 20-
80%
0 -
20%
Water soluble Surfactant (HLB > 12) 20 -
40%
20 -
50 %
30-
80%
Hydrophilic Co-solvent e.g PEG 0 –
40%
20 -
50%
0 -
50%
Classification based on the excipient in the Formulation

9. oil
surfactant
Co-
Surfacta
nt
Drug

10. Oil
Oils are the most important excipient.
Help in solubilizing the lipophilic drug in a high amount.
Facilitate self-emulsification and increase the fraction of
lipophilic drug transported.
Increase absorption from the GI tract.
Both long-chain triglyceride and medium-chain
triglyceride oils with different degrees of saturation have
been used for the formulation of SEDDSs.

11. List of oil used in SEDDS
Oils
• Corn oil,
• peanut oil,
• Oleic oil
• Olive oil
• Peppermint oil
• Captex 355
• Labrafac FCC,
• Sesame oil
• Hydrogenated soyabean oil
• Hydrogenated vegetable oils

12. Surfactant
Surfactant will Improve Bioavability By different mechanism
 Improve Drug dissolution
 Increase intestinal epithelial permeability
 Increased tight junction permeability
 Non-ionic surfactants with high hydrophilic–lipophilic balance (HLB)
values are used in formulation of SEDDSs
 Surfactant strength ranges between 30–60% w/w of the formulation
in order to form a stable SEDDS.
 A large quantity of surfactant may irritate the GIT.
 Non-ionic surfactants are less toxic as compared to ionic surfactants.

13. List of Surfactants
Surfactants HLB <10
Miglyol 840
Captex 200
Capmul MCC
Maisine 35-1
Labrafil M-2125 CS
Labrafil M1944 CS
Span 80
Span 20
Plurol Olique
Crill 4
Neobee M-20
Morlowet 4750
Surfactant HLB>10
Polysorbate 80
Polysorbate 20
Labrasole
Span 20
Crillet 4
Softigen 767
Liquid State
Surfactants HLB <10
Imwitor 988
Immvitor742
Gelucire43/01
Surfactant HLB>10
Gelucire 44/14
Gelucire 50/13
Vitamine E TPGS
Chremophore RH40
Chremophore EL
Labrafil M 2130 CS
Brij 96
Myrj 45
Semisolid State
Waxes: Yello Wax, Parraffin Wax,
Microcrystaline Wax, Carnuba Wax
Fatty Alcohole: Cetyl Alcohol, Steryl alcohol
Cetostyrile Alcohol

14.  Co- Surfactant/Co-solvents help to dissolve large amounts of
hydrophilic surfactants or the hydrophobic drug in the lipid
base.
 These solvents sometimes play the role as co-surfactant in the
micro-emulsion systems.
Co- solvent/Co-Surfactant
Co- solvent Co-Surfactant
Ethanol
Glycerin
Propylene glycol
PEG
Span 20
Span 80
Capryol 90
Lauroglycol

15. General Formulation Approaches
 solubility profiling studies for selection of oil.
 Drug excipient compatibility studies.
 Preparation of a series of SEDDS system containing
drug in various oil and surfactant with different
combinations.
 Optimization of formulation on the basis of in vitro
self-emulsification properties, droplet size analysis,
stability studies, robustness to dilution upon addition
to water under mild agitation conditions.

16. Mechanism of Self Emulsification.
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
In emulsification process the free energy (∆G) associated is
given by the equation:
where,
∆G = free energy associated with the process
N = number of droplets
r = Radius of droplets
б = interfacial energy

17. 2.GLOBULE SIZE.
SEDDS SMEDDS
100-300 nm <50 nm
40-80% <20%
3.Concentration of oil.

18. (1) Oral delivery:
(A)Self emulsifying capsule
(B) Self--Emulsifying sustained / controlled release tablet
(C) Self emulsifying sustained / controlled release pellets
(D)Self emulsifying solid dispersions:
(2) Topical Delivery:
(3) Oculars and Pulmonary delivery:
(4) Parenteral delivery:

19. lipids may enhance bioavailability via a number of potential
mechanisms, including.
a) Alterations (reduction) in gastric transit.
b) Increases in effective luminal drug solubility.
c) Stimulation of intestinal lymphatic transport
d) Changes in the biochemical barrier function
e) Changes in the physical barrier function of the GI tract.
f) The polarity of lipid phase is one of the factors that govern
the release from the micro-emulsion.

20. A) Capsule filling with liquid and semisolid self-emulsifying
formulations:
This is simplest and most common technology for
encapsulation of liquid or semisolid Self Emulsion for oral
route
Procedure for semisolid formulation
1) Heating of the semisolid excipient
2) Incorporation of the active substances (with stirring).
3) Capsule filling with the molt cooling to room
temperature.
4) Filling of the formulation into the capsules

21. B) Spray drying
.
Final SEDDS Lipid formulation
Solubilized liquid formulation is atomized into spray
droplet
Droplet introduce into drying chamber
Volatile phase evaporate into tablet pattern
Drying of product

22. C) Adsorption to solid carriers:
The adsorption process is simple and just
involves addition of the liquid On to carriers
by mixing in a blender. to obtain free flowing
powder

23. D) Melt granulation:
Melt granulation is a process in which powder
agglomeration is obtained through the addition of
a binder that melts or softens at relatively low
temperatures.
Melt extrusion is a solvent-free process that allows
high drug loading (60%), as well as content
uniformity. Extrusion is a procedure of product of
uniform shape and density, by forcing it through a die
under controlled temperature, product flow, and
pressure conditions.
E) Melt extrusion/extrusion spheronization:

24.  Thermodynamic Stability Studies.
 Centrifugation
 Freeze thaw cycle
 Heating Cooling Cycle
 Dispersibility test
 Turbidimetric Evaluation
 Viscosity Determination
 Droplet Size Analysis and Particle Size Measurements
 Refractive Index and Percent Transmittance
 Electro Conductivity Study
 In vitro Diffusion Study
 Drug Content
 In vivo permeability studies

25. 1. Thermodynamic Stability Studies.
It include the evaluation of stability of product include the
phase separation
 Incompatibility between formulation and gelatin shale
 Delay disintegration
 Incomplete drug release
a) Centrifugation Six cycles between refrigerator temperature
(40ºC) and 45ºC with storage at each temperature of not less than 48
hr is studied.
b) Heating Cooling Cycle formulations are centrifuged thaw
cycles between 21 ºC and +25 ºC with storage at temperature for not
less than 48 hr 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.
c) Freeze thaw cycle Three freeze for the formulations. Those
formulations passed this test showed good stability with no phase
separation, creaming, or cracking.

26. 2) Dispersibility test:-
using a standard USP XXII dissolution apparatus 2. One milliliter
of each formulation was added to 500 mL of water at 37 ± 0.5 0C.
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 Grading system:
3) Turbidimetric Evaluation:
Nephelo turbidimetric evaluation is done to monitor the
growth of emulsification. Fixed quantity of Selfemulsifying
system is added to fixed quantity of suitable medium (0.1N
hydrochloric acid) under continuous stirring (50 rpm) on
magnetic plate at ambient temperature, and the increase in
turbidity is measured 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),

27. 4) Viscosity Determination
The SEDDS system is generally administered in soft gelatin or
hard gelatin capsules. So, it can be easily pourable into capsules
and such system should not too thick to create a problem. The
rheological properties of the micro emulsion are evaluated by
Brookfield viscometer. This viscosities determination conform
whether the system is w/o or o/w. If system has low viscosity
then it is o/w type of the system and if high viscosities then it are
w/o type of the system.
5) Droplet Size Analysis 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.

28. In relation to formulation development of poorly
soluble drugs in the future, there are now
techniques being used to convert liquid/semi-solid
SEDDS and SMEDDS formulations into powders
and granules, which can then be further processed
into conventional 'powder-fill' capsules or even
compressed into tablets.
FUTURE TREND:
Hot melt granulation is a technique for producing
granules or pellets, and by using a waxy
solubilising agent as a binding agent, up to 25%
solubilising agent can be incorporated in a
formulation.

29. The main benefit of this approach is that pre-
dissolving the compound overcomes the initial rate
limiting step of particulate dissolution in the aqueous
environment within the GI tract. However, a
potential problem is that the drug may precipitate
out of solution when the formulation disperses in the
GI tract.

30. MARKETED PRODUCTS OF SEDDS

31. CONCLUSION
SMEDDS formulation can be optimized for the
delivery of hydrophobic compounds with drug
loading; minimum surfactant concentration and
proper infinite dilution can be achieved without drug
precipitation.
Self-emulsifying drug delivery system can be
use for the formulations of drugs compounds with
poor aqueous stability.
Development of this technology SEDDS will
continue to enable novel applications in drug
delivery system. SEDDS have been shown to be
reasonably successful in improving the oral
bioavailability of poorly water-soluble and Traditional
preparation of SEDDS involves dissolution of drugs in
oils and their blending with suitable solubilizing
agents.

32. P.A. Patel, et al Self Emulsifying Drug Delivery System: A Review,
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A.Kumar, et al Self Emulsifying Drug Delivery System (SEDDS):
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J.Tang, et al Preparation of Self-emulsifying Drug Delivery Systems
of Ginkgo biloba Extracts and In vitro Dissolution Studies. Asian
Journal of Traditional Medicines, 2006, 1,3-4 .
R. Sachan, et al Self-Emulsifying Drug Delivery System A Novel
Approach for enhancement of Bioavalibility. Pharm Tech
Res.2010,2(3) 1738-1745 .
M. Chitneni et al Intestinal Permeability Studies of Sulpiride
Incorporated in to self-microemulsifying drug delivery system
(smedds) Pak. J. Pharm. Sci., .24,2, April 2011,.113-121.