innovation in Liquid 2 by bhaumik and sachin seminar

Seminar on
RECENT INNOVATION IN
ORAL LIQUID DOSAGE FORM
DEPARTMENT OF PHARMACEUTICS
NOOTAN PHARMACY COLLAGE, VISNAGAR
Presented
By

Pool of contents:
Self emulsifying drug delivery system as oral
liquid
Self microemulsifying drug delivery system as
oral liquid
In-situ gel as oral liquid
Lyophilized suspension as oral liquid
2

SEDDS as oral liquid
1. INTRODUCTION:
SEDDS means self emulsifying drug delivery system
SEDDS are usually used to improve the
bioavailability of hydrophobic drugs.
SEDDS is ideally an isotropic mixture of oils and
surfactants and sometimes co solvents.
SEDDS can be orally administered in soft or hard
gelatin capsule and upon per oral administration,
these systems form fine emulsions in the GIT with
mild agitation provided by gastric mobility.
3

self emulsifying drug delivery process depends on:
1. Nature of the oil-surfactant pair
2. Concentration of surfactant
3. Temperature at which self-emulsification occurs.
4

•OILS
•SURFACTANT
•COSOLVENTE
1.
2.
3.
2. COMPOSITION OF SEDDS:
5

1. 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.
Long-chain triglyceride and medium-chain triglyceride
oils have been used in the design of SEDDS.
Novel semisynthetic medium-chain triglyceride oils
have surfactant properties and are widely replacing the
regular medium-chain triglyceride.
6

Nonionic surfactants with high hydrophilic-lipophilic
balance (HLB) values are used in formation of SEDDS
e.g. Tween, Labrasol, labrafac, cremophore. The usual
surfactant ranges b/w 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.
2. SURFACTANT:
7

Cosolvents like diethylene 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 systems.
3. COSOLVENTS:
8

The selection of oil, surfactant and
cosolvent based on the solubility of the
drug and the preparation of the phase
diagram.
The 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.
3. FORMULATION OF SEDDS:
9

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.
4. CHARACTERIZATION OF SEDDS:
a. Visual assessment:
This may provide important information about the self-
emulsifying and microemulsifying property of the
mixture and about the resulting dispersion.
10

b. Turbidity measurement:
This is to identify efficient self-emulsification by
establishing whether the dispersion reaches equilibrium
rapidly and in a reproducible time.
c. Droplet size:
This is a crucial factor in self-emulsification performance
because it determines the rate and extent of drug release
as well as the stability of the emulsion. Photon
correlation spectroscopy, microscopic techniques or a
Coulter Nanosizer are mainly used for the determination
of the emulsion droplet size. The reduction of the droplet
size to values below 50 nm leads to the formation of
SMEDDSs, which are stable, isotropic and clear o/w
dispersions.
11

d. Zeta potential measurement:
This is used to identify the charge of the droplets. In
conventional SEDDSs, the charge on an oil droplet is
negative due to presence of free fatty acids.
e. Determination of emulsification time:
Self-emulsification time, dispersibility, appearance and
flowability was observed.
5. APPLICATION OF SEDDS:
SEDDSs present drugs in a small droplet
size and well-proportioned distribution,
and increase the dissolution and
permeability.
12

SEDDSs protect drugs against hydrolysis
by enzymes in the GI tract and reduce the
presystemic clearance in the GI mucosa
and hepatic first-pass metabolism.
6. 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.13

7. DRAWBACKS OF SEDDS:
The drawbacks of this system include
chemical instabilities of drugs and high
surfactant concentrations. The large
quantity of surfactant in self-emulsifying
formulations (30-60%) irritates GIT.
Moreover, volatile Cosolvents 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. 14

15
8. MARKET PREPARATION SEDDS:

SMEDDS are defined as isotropic mixtures
of natural or synthetic oils, solid or 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.
1. INTRODUCTION:
SMEDDS as oral liquid
16

SEDDS SMEDDS
Droplet size between
100 and 300 nm
Oil phase 40-50%
Droplet size < 50 nm
Oil phase <20%
Difference b/w SEDDS & SMEDDS:
When compared with emulsions, which are sensitive and
metastable dispersed forms, SMEDDS are physically
stable formulations that are easy to manufacture.
The SMEDDS mixture can be filled in either soft or hard
gelatin capsules.
17

2. ADVANTAGES OF SMEDDS:
Improvement in oral bioavailability :
SMEDDS to present the drug to GIT in
solubilised and micro emulsified form
(globule size between 1-50 µm) and
subsequent increase in specific surface
area
E.g. In case of Halofantrine
approximately 6-8 fold increase in BA of
drug was reported in comparison to tablet
formulation.
18

Ease of manufacture and scale-up:
Ease of manufacture and scale up is one of
the most important advantage that makes
SMEDDS unique when compared to other
drug delivery systems like solid
dispersions, liposomes, nanoparticles, etc.,
dealing with improvement of BA.
Reduction in inter-subject and intra-subject
variability and food effects:
Several research papers specifying that,
the performance of SMEDDS is
independent of food and, SMEDDS offer
reproducibility of plasma profile are
available. 19

Ability to deliver peptides that are prone to enzymatic
hydrolysis in GIT:
SMEDDS ability to deliver
macromolecules like peptides, hormones,
enzyme substrates and inhibitors and their
ability to offer protection from enzymatic
hydrolysis.
No influence of lipid digestion process:
SMEDDS is not influenced by the lipolysis,
emulsification by the bile salts, action of
pancreatic lipases and mixed micelle
formation.
20

Increased drug loading capacity:
SMEDDS also provide the advantage of
increased drug loading capacity when
compared with conventional lipid solution
as the solubility of poorly water soluble
drugs with intermediate partition
coefficient (2<log P>4) are typically low in
natural lipids and much greater in
amphilic surfactants, co surfactants and
co-solvents.
21

3.ADVANTAGES OF SMEDDS OVER EMULSION:
SMEDDS can be easily stored since it
belongs to a thermodynamics stable
system.
Size of the droplets of SMEDDS is less as
compared to emulsion that’s why increase
in BA.
SMEDDS offer numerous delivery options
like filled hard gelatin capsules or soft
gelatin capsules or can be formulated in to
tablets whereas emulsions can only be
given as an oral solutions. 22

Emulsion can not be autoclaved as they
have phase inversion temperature, while
SMEDDS can be autoclaved.
PREPARATION AND EVALUATION OF SMEDDS
CONTAINING FENOFIBRATE:
4.
a. Introduction:
The present work was aimed at formulating a SMEDDS
of fenofibrate and evaluating its in vitro and in vivo
potential.
The optimized formulation for in vitro dissolution and
pharmacodynamic studies was composed of Labrafac
CM10 (31.5%), Tween 80 (47.3%), and polyethylene
glycol 400 (12.7%).
23

The SMEDDS formulation showed complete release in 15
minutes as compared with the plain drug, which showed
a limited dissolution rate.
The optimized formulation was then subjected to
stability studies as per International Conference on
Harmonization (ICH) guidelines and was found to be
stable over 12 months.
Thus, the study confirmed that the SMEDDS formulation
can be used as a possible alternative to traditional oral
formulations of fenofibrate to improve its bioavailability.
24

In all the formulations, the level of fenofibrate was kept
constant.
Briefly, accurately weighed fenofibrate was placed in a
glass vial, and oil, surfactant, and cosurfactant were
added. Then the components were mixed by gentle
stirring and vortex mixing and were heated at 40ºC on a
magnetic stirrer, until fenofibrate was perfectly
dissolved. The mixture was stored at room temperature
until further use.
A series of SMEDDS formulations were prepared using
Tween 80 and PEG 400 as the S/CoS combination and
Labrafac CM10 as the oil (Table 1).
b. Preparation:
25

Table 1. Developed Formulations With Their Compositions
26

c. Result and discussion:
Solubility study:
One important consideration when formulating a
self-emulsifying formulation is avoiding
precipitation of the drug on dilution in the gut
lumen in vivo. Therefore, the components used in
the system should have high solubilization
capacity for the drug, ensuring the solubilization
of the drug in the resultant dispersion. Results
from solubility studies are reported in Figure 1. As
seen from the figure, Maisine 35-1 and Labrafac
CM10 showed the highest solubilization capacity
for fenofibrate, followed by Tween 80 and PEG
400. Thus, for our study we selected Maisine 35-1
and Labrafac CM10 as oils and Tween 80 and PEG
400 as surfactant and cosurfactant, respectively. 27

Pseudoternary Phase Diagrams
Self-microemulsifying systems form fine oil-water
emulsions with only gentle agitation, upon their
introduction into aqueous media. Surfactant and
cosurfactant get preferentially adsorbed at the
interface, reducing the interfacial energy as well as
providing a mechanical barrier to coalescence. The
decrease in the free energy required for the
emulsion formation consequently improves the
thermodynamic stability of the microemulsion
formulation. Therefore, the selection of oil and
surfactant, and the mixing ratio of oil to S/CoS,
play an important role in the formation of the
microemulsion.
29

In the present study both Maisine 35-1 and
Labrafac CM10 were tested for phase behavior
studies with Tween 80 and PEG 400 as the S/CoS
mixture. As seen from the ternary plot (Figures 2
and 3), Labrafac CM10 gave a wider
microemulsion region than did Maisine 35-1 at all
S/CoS ratios. Thus, Labrafac CM10 was selected
as the preferred vehicle for the optimized
formulation. The microemulsion existence area
increased as the S/CoS ratio increased. However,
it was observed that increasing the surfactant ratio
resulted in a loss of flowability. Thus, an S/CoS
ratio between 3:1 and 4:1 was selected for the
formulation study.
30

PEG 400 is reported to be incompatible with hard
gelatin capsules when used in high concentrations.
Thus, while optimizing the S/CoS ratio, we tried
to keep the concentration of PEG 400 as low as
possible (<15% wt/wt of total formulation), as we
had a final aim of putting the SMEDDS
formulations into liquid-filled hard gelatin
capsules. Figure 4 shows phase diagrams in the
presence of the drug. As seen from the figure, the
inclusion of drug narrowed the microemulsion
existence area, because inclusion of the drug in the
lipid phase led to expansion of the lipid phase and
consequently a need for a higher S/CoS ratio for
stabilization.
33

d. Conclusions:
An optimized SMEDDS formulation consisting of
Labrafac CM10 (31.5% wt/wt), Tween 80 (47.3% wt/wt),
PEG 400 (12.7% wt/wt), and fenofibrate (8.5% wt/wt)
was successfully developed with an increased
dissolution rate, increased solubility, and, ultimately,
increased bioavailability of a poorly water-soluble drug,
fenofibrate. The developed formulation showed higher
pharmacodynamic potential as compared with plain
fenofibrate. Results from stability studies confirmed the
stability of the developed formulation. Thus, our study
confirmed that the SMEDDS formulation can be used as
a possible alternative to traditional oral formulations of
fenofibrate to improve its bioavailability.
35

DEVELOPMENT OF PROTOTYPE SELF-
EMULSIFYING LIPID BASED FORMULATIONS:
5.
a. Introduction:
It is well recognized that lipid-based formulations can
enhance oral bioavailability of poorly water-soluble
drugs. Lipid containing formulations can be an oil, an
emulsion or SEDDS. SEDDS are isotropic mixtures of
oil(s), surfactant(s), co-surfactant(s), co-solvent(s) and
drug. They form fine oil-in-water emulsions when
introduced into aqueous media under gentle agitation.
The potential of SEDDS for enhancing the bioavailability
of poorly soluble drugs has been evident for at least a
decade. One of the working hypotheses in the present
study is that particle size distribution of the emulsions
can influence the bioavailability. 36

b. Purpose:
To develop prototype lipid based self-emulsifying drug
delivery systems (SEDDS) and self-microemulsifying
drug delivery systems (SMEDDS) with the following
characteristics:
1. Clear single-phase pre-concentrate
2. Mono-modal particle size distribution
3. Digestible lipid containing formulation
with highest possible sesame oil content
37

c. Results and discussion:
A filled triangle indicates that the pre-concentrate is not single-phased.
An open circle indicates a single-phased preconcentrates that do not
self-emulsify. A filled circle indicates a single-phased and self-
emulsifying system (S(M)EDDS)
38

Figure 1 presents the physical appearance of the pre-concentrate and
its ability to selfemulsify as a function of the composition. Single-phased
and self-emulsifying preconcentrates are only obtained in two distinct
composition ranges. Furthermore it is shown that a concentration of
ethanol higher than 10% is needed for the pre-concentrate to be self-
emulsifying.
39

An open circle indicates a S(M)EDDS resulting in an (micro)emulsion
with a bi-modal (poly-disperse) particle size distribution. A filled circle
indicates S(M)EDDS resulting in an (micro)emulsion with a mono-modal
particle size distribution.
In figure 2 the particle size distribution of the resulting emulsions is
presented as either bimodal or mono-modal as a function of the
composition. The formulations with low Cremophor RH40 concentration
correspond to a SEDDS and the formulations with high Cremophor
RH40 concentration correspond to a SMEDDS.
d. Conclusion :
Different ratios of Maisine 35-1 and sesame oil have been tested but the
ratio 1:1 afforded the most promising self emulsifying systems.
Self-emulsifying systems with monomodal particle size distribution and
distinct different mean particle size have been developed.
Mean particle size for the mono-modal self-emulsifying systems is
dependent on the ratio between Cremophor RH40 and oil phase. 40

PREPARATION AND EVALUATION OF SMEDDS
CONTAINING NIFEDIPINE:
6.
a. Purpose:
To develop and characterize self-microemulsifying drug
delivery systems (SMEDDS) of nifedipine and to
evaluate their oral bioavailability in male Sprague-
Dawley albino rats.
b. Methods :
Solubility of nifedipine was determined in different
vegetable oils. Based on the solubility, sesame oil was
selected and pseudo-ternary phase diagram was
constructed using sesame oil, surfactants blend (Span
80 / Tween 80 at 3:7 ratio) and co surfactant (n-butanol)
at surfactant / co surfactant mixture ratio of 9:1.
41

Five SMEDDS were prepared by selecting different
proportions from the self-emulsifying region of pseudo-
ternary phase diagram. The SMEDDS were characterized
for the self-dispersibility, droplet size, drug content and
Fourier transformed-infrared spectroscopy (FT-IR). The
in vitro drug release from SMEDDS, pure drug and
commercial products was compared. The selected
SMEDDS and pure drug were orally administered to rats
and blood concentrations of nifedipine at different time
points were measured. T1/2, Tmax and AUC0-24 were
compared. Relative bioavailability of SMEDDS was
calculated.
42

c. Results:
All the SMEDDS showed good self-dispersibility, formed
clear microemulsions with very small droplet size (less
than 0.2 μm) and drug content was found to be within
the limits. FT-IR study showed that there is no
incompatibility between the SMEDDS ingredients
(sesame oil, Tween 80 and Span 80) and nifedipine. The
prepared SMEDDS showed faster drug release
compared to pure drug and the two selected commercial
formulations. All the prepared SMEDDS, pure drug and
commercial formulations followed first order release.
Some SMEDDS formulations gave the higher DE, Cmax,
Tmax, T½ and relative % BA as compared to pure drug
and commercial formulations.
43

d. Conclusion :
These results indicate the usefulness of the SMEDDS for
the improvement of the dissolution rate and thereby oral
bioavailability of poorly water soluble drugs like
nifedipine.
44

Self nano emulsifying
drug delivery system
The research project was done to develop a
self-nanoemulsifying drug delivery system
(SNEDDS) for non-invasive delivery of
protein drugs.
Eg. Fluorescent-labeled beta-lactamase
(FITC-BLM), a model protein, was loaded
into SNEDDS through the solid dispersion
technique.
45

In situ gel
1. INTRODUCTION:
In situ is a Latin word which translated
literally as ' In position ‘.
It is a drug delivery system which is in a
solution form before the administration in
the body but it converts in to a gel form
after the administration.
There are various routes such as oral, ocular,
vaginal, rectal, I/V , intraperitoneal etc…
46

2. ADVANTAGES:
Ease of administration.
Improved local bioavailability.
Reduced dose concentration.
Reduced dosing frequency.
Improved patients compliance.
Less investment and cost of manufacturing.
Prolonged delivery period.
47

Formulation of gels depends on factors like
temperature modulation, pH change,
presence of ions and ultra violet irradiation,
from which the drug gets released in a
sustained and controlled manner. Various
biodegradable polymers that are used for
the formulation of in situ gels include gellan
gum, alginic acid, xyloglucan, pectin,
chitosan, poly(DL lactic acid), poly(DL-
lactide-co- glycolide) & poly- caprolactone .
48

3. APPROACHES OF IN SITU GEL:
There are certain broadly defined
mechanisms used for triggering the in situ
gel formation of biomaterials:
Physiological stimuli (e.g., temperature
and pH),
Physical mechanism-changes in
biomaterials (e.g., swelling and solvent
exchange-Diffusion ),
Chemical reactions (e.g. ionic, enzymatic,
and photo-initiated polymerization).
49

a. In situ formulation based on physiological stimuli:
Thermally trigged system transitions from sol-gel is
triggered by increase or decrease in temperature 3
strategies: Negatively thermosensitive (poly N-
isopropylacrylamide ) Positively thermosensitive (poly
acrylicacid , polyacrylicamide ) Thermally
reversible( pluronics , tetronics ).
Positively thermosensitive: A positive temperature
sensitive hydrogel has an upper critical solution
temperature (UCST), such hydrogel contracts upon
cooling below the UCST. E.g. poly(acrylic acid) (PAA)
polyacrylamide ( PAAm ) poly( acrylamide -co-butyl
methacrylate )
50

Negatively thermosensitive: Negative temperature-
sensitive hydrogels have a lower critical solution
temperature (LCST) and contract upon heating above the
LCST E.g. Poly(N- isopropylacrylamide )[ PNIPAAm ].
water soluble at low LCST, hydrophobic above LCST.
The ideal critical temperature range for such system is
ambient and physiologic temperature, such that clinical
manipulation is facilitated and no external source of heat
other than that of body is required for triggering
gelation.
pH triggered systems : pH triggered systems With
increases external pH, Swelling of hydrogel increases if
polymer contains weakly acidic (anionic) groups ,
decreases if polymer contains weakly basic (cationic)
groups.
51

b. In situ formulation based on physical mechanism:
Swelling In situ formation may also occur when material
absorbs water from surrounding environment and
expand to cover desired space. One such substance is
Myverol (glycerol monooleate ), which is polar lipid that
swells in water to form lyotropic liquid crystalline phase
structures. It has some Bioadhesive properties and can
be degraded in vivo by enzymatic action Solvent
exchange-Diffusion This method involves the diffusion
of solvent from polymer solution into surrounding tissue
and results in precipitation or solidification of polymer
matrix. N-methyl pyrrolidone (NMP) has been shown to
be useful solvent for such system.
52

c. In situ formulation based on chemical reaction:
Following chemical reaction cause gelation:
Ionic cross linking: Ionic crosslinking Polymers may
undergo phase transition in presence of various ions.
Some of the polysaccharides fall into the class of ion-
sensitive ones. While K-carrageenan forms rigid, brittle
gels in reply of small amount of K + , i-carrageenan
forms elastic gels mainly in the presence of Ca 2+ .
Gellan gum commercially available as Gelrite® is an
anionic polysaccharide that undergoes in situ gelling in
the presence of mono- and divalent cations, including Ca
2+ , Mg 2+ , K + and Na + . Gelation of the low-methoxy
pectins can be caused by divalent cations, especially Ca
2+ . Likewise, alginic acid undergoes gelation in
presence of divalent/polyvalent cations e. g. Ca 2+ . 53

Enzymatic cross-linking: Enzymatic cross-linking
Cationic pH-sensitive polymers containing immobilized
insulin and glucose oxidase can swell in response to
blood glucose level, releasing the entrapped insulin in a
pulsatile fashion. Adjusting the amount of enzyme also
provides a convenient mechanism for controlling the
rate of gel formation, which allows the mixtures to be
injected before gel formation.
Photo-polymerization: A solution of monomers or
reactive macromer and initiator can be injected into a
tissues site and the application of electromagnetic
radiation used to form gel . long wavelength ultraviolet
and visible wavelengths are used. Short wavelength
ultraviolet is not used because it has limited penetration
of tissue and biologically harmful . Initiator 2,2
dimethoxy-2-phenyl acetophenone in ultraviolet light ,
Camphorquinone and ethyl eosin in visible light used.54

4. POLYMERS USED IN IN SITU GEL:
a. Natural :
b. Synthetic :
Pectin
Xyloglucan
Xanthan gum
Gellan gum
Chitosan
Carbopol
Aliphatic polyesters
Thermosetting polymers 55

5. CLASSIFICATION OF IN SITU DDS:
a. Oral delivery :
Pectin, xyloglucan and gellan gum are the
natural polymers used for in situ forming
oral drug delivery systems. pectin is water
soluble. Xyloglucan forms thermally
reversible gels on warming to body
temperature. slow gelation time (several
minutes) that would allow in situ gelation
in the stomach following the oral
administration of chilled xyloglucan
solution.
56

b. Occular delivery :
The following characteristics are required
to optimize ocular drug delivery systems:
A good corneal penetration.
A prolonged contact time with corneal
tissue.
Simplicity of installation for the patient.
A non- irritative and comfortable form.
Appropriate rheological properties and
concentration.
57

Ocular- delivery Polymer used :-
Gellan gum
Alginic acid
Xyloglucan
Drug used for Ocular in situ drug
delivery:-
Antimicrobial agents
Antiinflammatory agents
Autonomic drugs used to relieve
intraocular tension in glaucoma.
58

These systems have the advantages :
Prolonged drug release.
Reduced systemic side effects.
Reduced number of applications.
Better patient compliance.
Generally more comfortable than insoluble
or soluble insertion.
Less blurred vision as compared to
ointment.
59

c. Nasal delivery :
Gellan gum and Xanthan gum were used
as in situ gel forming polymers.
 An in situ gel system for nasal delivery of
mometasone furoate was developed and
evaluated for its efficacy for the treatment
of allergic rhinitis.
The formulation was in solution form at
room temperature that transformed to a
gel form when kept at 37°.
60

Animal experiments demonstrated
hydrogel formulation to decrease the
blood-glucose concentration by 40-50% of
the initial values for 4-5 h after
administration with no apparent
cytotoxicity.
Nasal in situ drug delivery system is
suitable for protein and peptide drug
delivery through nasal route.
61

d. Rectal and vaginal delivery :
Miyazaki et al . investigated the use of
xyloglucan based thermo reversible gels
for rectal drug delivery of indomethacin.
Administration of indomethacin loaded
xyloglucan based systems to rabbits
indicated broad drug absorption peak and
a longer drug residence time as compared
to that resulting after the administration of
commercial suppository.
62

For a better therapeutic efficacy and
patient compliance, mucoadhesive ,
thermosensitive , prolonged release
vaginal gel incorporating clotrimazole - β-
cyclodextrin complex was formulated for
the treatment of vaginitis .
It also indicated the avoidance of adverse
effects of indomethacin on nervous
system.
63

d. Injectable delivery :
A novel, Injectable, thermosensitive in situ
gelling hydrogel was developed for tumor
treatment This hydrogel consisted of drug
loaded chitosan solution neutralized with
β-glycerophosphate. Local delivery of
paclitaxel from the formulation injected
intratumorally was investigated using
EMT-6 tumors, implanted subcutaneously
on albino mice in situ forming gels were
used for preventing postoperative
peritoneal adhesions thus avoiding pelvic
pain, bowel obstructions and infertility. 64

6. EVALUATION OF IN SITU GEL:
a. Gelation temperature :
The gelation temperature was determined
by heating the solution (1-20
c) min in a test
tube with gentle stirring until gel was
formed. The gel was said to have formed
when there was no flow after container
was overturned.
65

b. Gelling capacity :
The gelling capacity of the formed gel was
determined visual inspection and the
different grades were allotted as per the
gel integrity, weight and rate of formation
of gel with respect to time.
66

c. Measurement of gel strength:
A sample of 50 gm of gel was placed in a
100 ml graduated cylinder and gelled in a
thermostat at 370
c. The apparatus for
measuring gel strength (weigh or
apparatus as shown in figure 1, weighing
27 gm) was allowed to penetrate in gel.
The gels strength, which means the
viscosity of the gels at physiological
temperature, was determined by the time
(seconds), the apparatus took to sink 5 cm
down through the prepared gel.
67

d. Determination of pH:
The pH of the gel was determined using a
calibrated pH meter. The readings were
taken for average of 3 samples.
e. Determination of mucoadhesive force:
The mucoadhesive force of all the
optimized batches was determined as
follows, a section of mucosa was cut from
the chicken cheek portion and instantly
fixed with mucosal side out onto each
glass vial using rubber band.
69

The vials with chicken cheek mucosa were
stored at 370
C for 5 minute then next vial
with a section of chicken cheek mucosa
was connected to the balance in inverted
position while first vial was placed on a
height adjustable pan. In situ gel was
added onto the mucosa of first vial. Then
the height of second vial was so adjusted
that the mucosal surfaces of both vials
come in intimate contact. Two minutes
time of contact was given. Then weight
was kept rising in the pan until vials get
detached. 70

Mucoadhesive force the minimum weight
required to detach two vials. The mucosa
was changed for each measurement.
71

f. Viscosity study:
Viscosity and rheology measured using
Brookfield rheometer or some other type
of viscometers such as Ostwald's
viscometer. The viscosity of these
formulations should be such that no
difficulties are arised during their
administration by the patient, especially
during parenteral and ocular
administration.
72

g. Spreadability study:
For the determination of Spreadability,
excess of sample was applied in between
two glass slides and was compressed to
uniform thickness by placing 1000 g
weight for 5 min. weight (50 g) was added
to the pan. The time in which the upper
glass slide moves over to the lower plate
was taken as measure of Spreadability (S).
S= ML/T
Where, M = weight tide to upper slide.
L = length moved on the glass slide.
T = time taken. 73

h. Content uniformity:
Buccal cavity of Isolation of chicken cheek
mucosa from the anterior healthy chicken
was obtained from the local slaughter
house. It was cleaned and the mucosa was
re-moved from the anterior buccal cavity.
The mucosa was stored in normal saline
with few drops of gentamycin sulphate
injection, to avoid bacterial growth. After
the removals of blood from the mucosal
surface it become ready for use.
75

i. Diffusion medium:
Assembly of diffusion cell for in-vitro
diffusion studies the oral diffusion cell was
designed as per the dimension given.
The diffusion cells were placed on the
magnetic stirrers. The outlet of the
reservoir maintained at 37±0.50
C and was
connected to water jacket of diffusion cell
using rubber latex tubes. The receptor co
presentment was filled with fluid.
76

The prepared chicken cheek mucosa was
mounted on the cell carefully so as to
avoid the entrapment of air bubble under
the mucosa. Intimate contact of mucosa
was ensured with receptor fluid by placing
it tightly with clamp. The speed of the
sitting was kept content throughout the
experiment .With the help of micropipette
1ml of sample was withdrawn at a time
intervals of 30 min. from sampling port of
receptor compartment & same volume was
the replaced with receptor fluid solution in
order to maintain sink condition. 77

The samples were appropriately diluted
and the absorbance was measured at ---
nm using Schimadzu 1700UV-VIS
spectrophotometer.
78

7. CONCLUSION:
The primary requirement of a successful
controlled release product focuses on
increasing patient compliance which the in
situ gels offer.
Exploitation of polymeric in- situ gels for
controlled release of various drugs
provides a number of advantages over
conventional dosage forms. Sustained and
prolonged release of the drug, good
stability and biocompatibility
characteristics make the in situ gel dosage
forms very reliable.
79

Use of biodegradable and water soluble
polymers for the in situ gel formulations
can make them more acceptable and
excellent drug delivery systems.
8. DEVELOPMENT OF A NOVEL IN SITU GEL
SYSTEM FOR ORAL DRUG DELIVERY
a. Purpose :
The aim of this investigation was to
develop a novel chitosan-glyceryl
monooleate (GMO) gel system that can be
used for sustained oral delivery of drugs.
80

b. Method :
Ketoprofen and dexamethasone were used
as the model hydrophilic and hydrophobic
drugs, respectively.
The optimal delivery system comprised of
chitosan, 3% (w/v) and GMO, 3% (w/v) in
0.33 M citric acid containing 1% (w/v)
ketoprofen or 0.03% (w/v) of
dexamethasone.
In vitro release of drug was carried out by
adding 1.0 ml of the solution to 40ml of
Sorensen’s phosphate buffer (pH=7.4). 81

The in situ gel formed was shaken in a
water bath at 80 rpm and 37°C. Drugs
were analyzed by HPLC. Effect of
crosslinking (glutaraldehyde, 50% v/v) on
the in vitro drug release was evaluated.
c. Result :
Use of citric acid to dissolve the chitosan
produced an optimal gel at pH 7.4 as
compared to acetic, lactic, and tartaric acid.
Incorporation of GMO into the gel
minimized the initial burst effect of the
drugs and enhanced its bioadhesive
property. 82

83
The drug release from such a gel followed
a matrix diffusion controlled mechanism.
d. Conclusion :
A novel in situ gel formulation containing
chitosan and GMO was developed and
tested. The in vitro release of ketoprofen
and dexamethasone from such gel was
found to be quick but could be controlled
by incorporation of a cross linker. This
novel chitosan-GMO system, with its
enhanced bioadhesive property, can be
used for sustained and targeted delivery of
a wide range of drugs.

84
Lyophilized
suspension
1. Lyophilized Lecithin Based Oil-Water
Microemulsions as a New & Low Toxic Delivery
System for Amphotericin B
a. Purpose :
To develop and investigate
lecithin based oil-water
microemulsions as potential
amphotericin B (AmB)
delivery systems and to
evaluate their in vivo acute
toxicity.

85
b. Method :
AmB was added to the microemulsion and
its location was evaluated by partitioning
studies and UV-visible spectrophotometric
analysis of the drug. Both, non-lyophilized
and reconstituted microemulsions were
characterized and assessed for their
stability. Single-dose acute toxicity of the
AmB microemulsion was studied on male
albino Webster-derived CD-1 mice and
compared with Fungizone®.

86
c. Result :
The studies performed showed that AmB
was intercalated on the oil-water interface
of the microemulsion as a complex formed
with lecithin molecules.
AmB addition did not seem to modify the
rheological properties of the original
system, but had an effect on its particle
size distribution.
Lyophilization of the microemulsion led to
an oily cake, easily reconstituted and
stable at the conditions studied.

87
Single-dose acute toxicity studies proved
that the LD50 of AmB microemulsions was
of 4 mg kg–1
of animal weight, compared
with 1 mg kg–1
found for Fungizone®.
d. Conclusion :
Lyophilized lecithin based oil-water
microemulsions appear to be valuable
systems for the delivery of AmB in terms
of easy and low-cost manufacturing,
stability and safety compared with the
formulations already in market.

88
References:
88
 From Wikipedia, the free encyclopedia
 Pouton CW. Lipid formulations for oral administration of drugs: non-
emulsifying, self-emulsifying and ‘self-microemulsifying’ drug delivery
systems. Eur J Pharm Sci. 2000;11:S93-S98.
PubMed DOI: 10.1016/S0928-0987(00)00167-6
 Constantinides PP. Lipid microemulsions for improving drug dissolution
and oral absorption: physical and biopharmaceutical aspects. Pharm
Res. 1995;12:1561-1572.
PubMed DOI: 10.1023/A:1016268311867
 The AAPS Journal 2007; 9 (3) Article 41 (http://www.aapsj.org).
 The Biopharmaceutics Classification System (BCS) Guidance, Office of
Pharmaceutical Science. Available from:
http://www.fda.gov/cder/OPS/BCS_guidance.htm [last accessed on 2008
Jan 12].

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