INTRODUCTION[1-5]:
Topical drug delivery can be defined as the
application of a drug containing formulation to the skin to directly treat the
cutaneous disorders. The topical drug delivery system is generally used where
other routes like oral, sublingual, rectal, parental of drug administration
fails or in local skin infection like a fungal infection. Human skin is a
uniquely engineered organ that permits terrestrial life by regulating heat and
water loss from the body whilst preventing the ingress of noxious chemicals or
microorganisms. It is also the largest organ of the human body, providing
around 10% of the body mass of an average person, and it covers an average area
of 2 sq. m. While such a large and easily accessible organ apparently offers
ideal and multiple sites to administer therapeutic agents for both local and
systemic actions, human skin is a highly efficient self-repairing barrier
designed to keep the insides in and the outside. Many widely used topical
agents like ointments, creams and lotions have numerous disadvantages. They are
usually very sticky causing uneasiness to the patient when applied. Moreover,
they also have less spreading co-efficient and need to apply with rubbing. They
also exhibit the problem of stability, due to all these factors, within the
major group of semisolid preparations; the use of transparent gels has
increased both in cosmetics and in pharmaceutical preparations. A gel is
colloid that is typically 99% by weight liquid, which is immobilized by surface
tension between it and a macromolecular network of fibers built from a small
amount of a gelatinous substance present. Gels are a relatively newer class of
dosage form created by entrapment of large amounts of aqueous or hydro
alcoholic liquid in a network of colloidal solid particles. Gel formulations
generally provide faster drug release compared with ointments and creams
pastes. In spite of the many advantages of gels, a major limitation is their
inability to deliver hydrophobic drugs. The water insoluble drug is not
directly incorporated into a gel base system. So to overcome this limitation an
emulsion based approach is being used so that a hydrophobic therapeutic moiety
can be successfully incorporated and delivered through gels. Firstly the
emulsion or microemulsion prepared and it’s evaluated and this microemulsion
incorporated in suitable gelling agent. When gels and emulsions are used in
combined form the dosage forms are referred as microemulsion based gel. In
fact, the presence of a gelling agent in the water phase converts a classical
emulsion into a microemulsion based gel. Direct oil-in-water system is used to
entrap lipophilic drugs whereas hydrophilic drugs are encapsulated in the reverse
water-in-oil system. Microemulsions possess a certain degree of elegance and
are easily washed off whenever desired. They also have a high ability to
penetrate the skin.
Drug
permeation through the skin:
Pathway of transdermal permeation:
1. Transdermal permeation, through the stratum
corneum.
2. Intercellular permeation, through the stratum
corneum.
3. Transappendageal permeation, via the hair
follicle, sebaceous and sweat glands.
The skin acts as a major barrier for permeation of
any substance into the body and this is mainly due to the stratum corneum,
which is its outer layer. In most of its areas, there are 10-30 layers of
stacked coneocytes with palms and soles having the most. Each corneocytes is
surrounded by a protein envelope and is filled with water-retaining keratin
proteins. The cellular shape and orientation of the keratin proteins add
strength to the stratum corneum. When a formulation is applied onto the skin,
several gradients are established across it, and drugs, to a certain extent,
are able to pass through the stratum corneum. It is also reported that one
important factor for drugs to permeate stratum corneum is the water gradient,
which can be altered by application of several formulation onto the skin.
Hence, for effective drug delivery through the skin, an external water gradient
could be established. Drugs, when applied onto the skin, can penetrate it via
three major routes viz., through sweat glands, stratum corneum or hair
follicles.
There has been a continuous effort for
understanding the structural barrier and properties of stratum corneum. The
permeation of drugs through hair follicles compared to the stratum corneum is
also widely being discussed. Further, it is reported that the follicular route
is more favorable for permeation of polar molecules as their influx through the
stratum corneum is difficult. There are specific factors which determine the
efficiency of drug permeation through the skin. The physicochemical nature of
drug, site and condition of skin, the formulations, and their influence on the
properties of stratum corneum are also important [6].
Basic
principle of permeation [7, 8]:
It is
well known that substances usually penetrate the skin by three different
routes: through the stratum corneum between the corneocytes (intercellular
route); through these cells and the intervening lipids (intracellular route);
or through the skin appendages, such as hair follicles and sweat glands.
Molecules with adequate solubility in water and oil, with a log of oil/water partition
co-efficient between 1 and 3 and a molecular weight lower than 0.6 kDa, may
penetrate the skin.
Therefore,
topical administration is limited to hydrophobic and low-molecular weight
drugs. Because most anticancer drugs are hydrophilic, have low oil/water
partition co-efficient, high molecular weights and ionic characters, they do
not easily penetrate the stratum Corneum.
Drug
permeation through the stratum corneum can be described by Ficks’s second law;
Where,
J is the flux, Dm is the diffusion co-efficient of the drug in the membrane, Cv
is the drug concentration in the vehicle, P is the drug partition co-efficient
and L is the stratum corneum thickness.
Mechanism
of drug absorption:
Permeation
of a drug involves the following steps:
·
Sorption by stratum corneum.
·
Penetration of drug through viable epidermis.
·
Uptake of the drug by the capillary network in the dermal papillary layer.
This
permeation can be possible only if the drug possesses certain physicochemical properties. The rate of permeation across the skin (dQ/dt) is
given by:
----------1.
Where,
Cd and Cr are the concentration of skin penetration in the donor compartment
(E.g., on the surface of the stratum corneum) and in the receptor compartment
(E.g., body) respectively. Ps is the overall permeability co-efficient of the
skin tissues to the penetrate. This permeability co-efficient is given by the
relationship:
--------------------2.
Where,
Ks is the partition co-efficient for the interfacial partitioning of the
penetrate molecular form a solution medium onto the stratum corneum, Dss is the
apparent diffusivity for the steady state diffusion of the penetrate molecule
through a thickness of skin tissues and Hs is the overall thickness of the skin
tissues. As Ks, Dss and Hs are constant under given condition, the permeability
co-efficient (Ps) for skins penetrate can be considered to be constant.
From
equation (1) it is clear that a constant rate of the drug permeation can be
obtained when Cd >> Cr i.e., the drug concentration at the surface of the
stratum corneum (Cd) is consistently and substantially greater than the drug
concentration in the body (Cr).
The
equation (1) becomes:
--------------------3.
And
the rate of skin permeation (dQ/dt) is constant provide the magnitude of Cd
remains fairly constant throughout the course of skin permeation. For keeping
Cd constant, the drug should be released from the device at a rate (Rr) that is
either constant or greater than the rate of skin uptake (Ra) i.e., Rr >>
Ra [9].
Factors affecting topical absorption of the
drug: [4,10]
Physiological Factors:
1.
Skin thickness
2.
pH of skin
3.
Lipid content
4.
Blood flow
5.
Hydration of skin
6.
Density of hair follicles
7.
Inflammation of skin
8.
Disease condition
9.
Density of sweat glands
Physiochemical Factors:
1.
Effect of vehicles
2.
Partition co-efficient
3.
Molecular weight (<400 Dalton)
4.
Degree of ionization (Only unionized drugs get absorbed well)
Ideal properties of microemulsion based
gel: [11]
1. Should be inert, compatible with
other additives
2. Should be free from microbial
contamination
3. Should be non-toxic
4. Should be economical
5. Should be maintained all
rheological properties of the gel
6. Should be washed with water and
free from staining nature
7. Should be convenient in handling
and its application
8. Should be stable at storage
condition
Advantages of microemulsion based gel:[7,12-17]
1. Better stability: Other
Transdermal preparations are comparatively less stable than microemulsion based
gel. Like powders are hygroscopic, creams shows phase inversion or breaking and
ointment shows rancidity due to oily base and normal topical emulsion shows
creaming effect. The microemulsion based gel does not show any above problems
and gives better stability.
2. Better loading capacity: Other
novel approaches like niosomes and liposomes are of nano size and due to
vesicular structures may result in leakage and result in lesser entrapment
efficiency. But gels due to vast network have comparatively better loading
capacity of the drug.
3. Production feasibility and low
preparation cost: Preparation of microemulsion based gel is comprised of
simpler and short steps which increases the feasibility of the production.
There are no specialized instruments needed for the production of microemulsion
based gel. Moreover, the materials used are easily available and cheaper.
Hence, decreases the production cost of microemulsion based gel.
4. Incorporation of hydrophobic
drugs: Most of the hydrophobic drugs cannot be incorporated directly into the
gel base because the solubility act as a barrier and a problem occurs during
the release of the drug, mainly class VI drug. Microemulsion based gel helps in
the incorporation of hydrophobic drugs into the oil phase and then oily
globules are dispersed in an aqueous phase resulting in o/w emulsion. And this
emulsion can be mixed into gel base. This may be proving better stability and
release of drug than simply incorporating drugs into gel base. E.g.,
ketoconazole, fluconazole, etc.
5. No intensive sonication:
Production of vesicular molecules needs intensive sonication which may result
in drug degradation and leakage. But this problem is not seen during the
production of microemulsion based gel as no sonication is needed.
6. To avoid the first pass effect
that is the initial pass of the drug substance through the systemic and partial
circulation following gastrointestinal absorption, avoiding the deactivation by
digestive and liver enzymes.
7. Controlled release:
Microemulsion based gel can be used to prolong the effect of drugs having
shorter t1/2.
8. They can avoid gastrointestinal drug
absorption difficulties caused by gastrointestinal pH and enzymatic activity
and drug interaction with food and drinks.
9. The use of microemulsion as delivery system
can improve the efficacy of a drug, allowing the total dose to be reduced and
thus minimizing side effects.
10. Microemulsion increase the rate of
penetration to the skin barrier so, ultimately increases the rate of absorption
and bioavailability.
11. Provides protection from hydrolysis and
oxidation as a drug in the oil phase in o/w microemulsion is not exposed to
attack by water and air.
12. They are less greasy in nature
and can be easily removed from the skin.
13.
Microemulsion
gel is non-invasive and increase patient compliance.
14. Reduction of dose as comparable
to the oral dosage form.
Disadvantages of microemulsion based gel:[7,12-17]
1. The larger particle size drugs
not easy to absorb through the skin.
2. Poor permeability of some drugs
through the skin.
3. Can be used only for drugs which
require very small plasma concentration for action.
4. Possibility of allergenic
reactions.
5. An enzyme in the epidermis may
denature the drugs.
Application of microemulsion based gel
[18] :
1. Enhance the transdermal
permeation of drugs significantly compared to conventional formulations such as
solutions, gels or creams.
2. They are able to incorporate
both hydrophilic (5-fluorouracil, apomorphine hydrochloride, diphenhydramine
hydrochloride, tetracaine hydrochloride, methotrexate etc.) and lipophilic
drugs (estradiol, finasteride, ketoprofen, meloxicam, felodipine, triptolide,
etc.) and enhance their permeation.
3. A large amount of drug can be
incorporated in the formulation due to the high solubilizing capacity.
4. Increase thermodynamic activity
towards the skin, the permeation rate of the drug from microemulsion may be
increased, since the affinity of a drug to the internal phase in microemulsion
can be easily modified to favour partitioning into the stratum corneum.
5. Using different internal phase,
changing its portion in microemulsion, the surfactant and co-surfactant in the
microemulsions may reduce the diffusional barrier of the stratum corneum by
acting as penetration enhancers.
6. The percutaneous absorption of
drug will also increase due to the hydration effect of the stratum corneum if
the water content in microemulsion is high enough.
Formulation consideration for microemulsion
based gel [4,5,14,19]:
1. Drug substances:
Mainly NSAIDs, antifungal agent,
antibacterial agent, etc. used. The judicious choice of the drug plays an
important role in the successful development of a topical product. The
important drug properties that affect its diffusion through the device as well
as through the skin are as follows:
a. Physicochemical properties:
• Adequate lipophilicity of the drug must
be required.
• Molecular weights of drug should be less
than 500 Daltons.
• Drugs which are highly acidic or alkaline
in solution are not suitable candidates for topical delivery.
• A pH of aqueous solution (saturated) of
drug should be required value between 5 and 9.
b. Biological properties:
• The drug should not stimulate an immune
reaction in the skin.
• The drug should not be directly irritated
to the skin.
• Tolerance to the drug must not develop
under the near zero order release profile of topical delivery.
• Drugs, which degrade in the
gastrointestinal tract or are inactivated by hepatic first pass effect, are
suitable for topical delivery.
2. Vehicle:
Six primary considerations guide the
development of a vehicle. The vehicle must:
• Deliver the drug to the directly target
site.
• Release the drug so it can migrate freely
to the site of action.
• Efficiently deposit the drug on the skin
with even distribution.
• Sustain a therapeutic drug level in the
target tissue for a sufficient duration to provide a pharmacological effect.
• Be appropriately formulated for the
anatomic site to be treated.
• Be cosmetically
acceptable to the patient.
Due to the efficiency of the epidermal
barrier, the amount of topical drug that gets through the stratum corneum is
generally low. Rate and extent of absorption vary depending on characteristics
of the vehicle, but is also influenced by the active agent itself.
a. Aqueous material:
This forms the aqueous phase of
microemulsion. Most commonly, water is used as aqueous phase. The pH of the
aqueous phase always needs to be adjusted due to its considerable impact on
phase behavior of microemulsion. The commonly used agents are water, alcohols,
etc.
b. Oils:
The oils used for preparation of microemulsion
having the capacity to solubilize the drug. For externally applied
microemulsions, mineral oils, either alone or combined with soft or hard
paraffin, are widely used both as the vehicle for the drug and for their
occlusive and sensory characteristics. Widely used oils in oral preparations
are non-biodegradable mineral and castor oils that provide a local laxative
effect, and fish liver oils or various fixed oils of vegetable origin (E.g.,
arachis, cottonseed, and maize oils) as nutritional supplements. Some are as
light liquid paraffin, isopropyl myristate, isopropyl stearate, isopropyl
palmitate, propylene glycol, etc.
3. Emulsifiers:
Emulsifying agent consists of surfactant
and co-surfactant, their concentration should be used in different proportion.
Emulsifying agents are used both to promote emulsification at the time of
manufacture and to control stability during a shelf life that can vary from
days for extemporaneously prepared microemulsions to months or years for
commercial preparations (E.g., polyethylene glycol 40 stearate, sorbitan
monooleate, span 80, polyoxyethylene sorbitanmonooleate, tween 80, stearic acid
and sodium stearate).
4. Penetration enhancers:
These are compounds which promote skin
permeability by altering the skin as a barrier to the flux of desired penetrate
and are considered as integral part of the most topical formulation. E.g.,
water, essential oils, urea and its derivatives, etc.
v Ideal characteristics of
penetration enhancers [20, 21]:
Ideally, penetration enhancers reversibly
reduce the barrier resistance of the stratum corneum without damaging viable
cells. Some of the more desirable properties for penetration enhancers acting
within the skin have been given as:
• They should be non-toxic, non-irritating
and non-allergenic.
• They should have no pharmacological
activity within the body.
• They would ideally work rapidly; the
activity and duration of effect should be both predictable and reproducible.
• The penetration enhancers should work
unidirectional, i.e., they should allow therapeutic agents into the body whilst
preventing the loss of endogenous materials from the body.
• They should be cosmetically acceptable
with an appropriate skin feel.
• When removed from the skin, barrier
properties should return both rapidly and fully to normal.
5. Gelling Agents:
These are the agents used to increase the
consistency of any dosage form and can also be used as a thickening agent. The
examples of gelling agent or polymers are given in Table 1.
Table.1 Gelling agents/polymers
used in microemulsion based gel
|
Natural
polymers
|
Semi
synthetic polymers
|
Synthetic
polymers
|
|
a.
Proteins
|
a.
Cellulose derivatives
|
a.
Carbomer
|
|
Collagen
|
Carboxymethyl
cellulose
|
Carbopol-940
|
|
Gelatin
|
Methylcellulose
|
Carbopol-934
|
|
b.
Polysaccharides
|
Hydroxy
propyl cellulose
|
Carbopol-941
|
|
Agar
|
Hydroxy
propyl methyl cellulose
|
b.
Poloxamer
|
|
Alginic
acid
|
Hydroxyethyl
cellulose
|
c.
Polyacrylamide
|
|
Sodium
or Potassium carrageenan
|
|
d.
Polyvinyl alcohol
|
|
Tragacanth
|
|
e.
Polyethylene and its copolymers
|
|
Pectin
|
|
|
|
Guar
Gum
|
|
|
|
Cassia
Tora
|
|
|
|
Xanthan
Gum
|
|
|
|
Gellan
Gum
|
|
|
6. Preservatives:
Used to resist microbial attack.
Examples- Methyl paraben, Propyl paraben.
7. Surfactants:
Various nonionic surfactants such as tween,
labrasol, labrafac CM 10, cremophore, etc. with high HLB values, can be used in
combination with oils to facilitate emulsification. Emulsifiers from natural
origin are preferred because of their safety profile compared to synthetic
emulsifiers. Nonionic surfactants are known to be less toxic than ionic
surfactants. The surfactant chosen must be able to lower the interfacial
tension to a very small value which facilitates the dispersion process during
the preparation of the microemulsion and provide a flexible film that can
readily deform around the droplets and be of the appropriate lipophilic
character to provide the correct curvature at the interfacial region. The
general surfactant concentration in the microemulsion formulation ranges
between 30-60% w/w. Surfactants with high HLB (>12) values assist the
immediate formation of o/w droplet and rapid spreading of the formation in
aqueous media [22].
Example: Sodium lauryl sulphate, sodium
glycolate.
8. Co-surfactants:
In most of the cases, single chain
surfactants alone are incapable to reduce o/w interfacial tension sufficiently
to form microemulsion. Owing to its amphiphilic nature, a co-surfactant
accumulates substantially at interface layer, increasing the fluidity of
interfacial film by penetrating into the surfactant layer. Short to medium
chain length alcohols are generally added as co-surfactants helping in
increasing the fluidity of interface [20]. Amongst short chain
alkanols, ethanol is widely used as permeation enhancer. In medium chain
alcohols 1-butanol was reported to be a most effective enhancer. The
surfactants and co-surfactant ratio is a key factor for phase properties [23].
9. Chelating agent:
Bases and medicaments in gels are sensitive
to heavy metals, hence added to protect.
Example: E.D.T.A., methylated cyclodextrin.
Methods of preparation of microemulsion[24]:
1. Phase Titration
Method:
Microemulsions are
prepared by the spontaneous emulsification method (phase titration method) and
can be depicted with the help of phase diagrams. Construction of phase diagram
is a useful approach to study the complex series of interactions that can occur
when the different components are mixed. Microemulsions are formed along with
various association structures (including emulsions, micelles, lamellar,
hexagonal, cubic, and various gels and oily dispersion) depending on the
chemical composition and concentration of each component. The understanding of
their phase equilibrium and demarcation of the phase boundaries are essential
aspects of the study. As quaternary phase diagram (four component system) is
time consuming and difficult to interpret, the pseudo ternary phase diagram is
often constructed to find the different zones including microemulsion zone, in
which each corner of the diagram represents 100% of the particular component Figure
(1). The region can be separated into w/o or o/w microemulsion by simply
considering the composition, that is, whether it is oil rich or water rich.
Observations should be made carefully so that metastable systems are not
included.
Figure1:
Pseudoternary phase diagram of oil, water and surfactant showing
microemulsion region
2. Phase Inversion Method:
Phase inversion of
microemulsion occurs upon addition of excess of the dispersed phase or in
response to temperature. During phase inversion, drastic physical changes
occur, including changes in particle size that can affect drug release both
in-vivo and in-vitro. These methods make use of changing the spontaneous
curvature of the surfactant. For non-ionic surfactants, this can be achieved by
changing the temperature of the system, forcing a transition from an o/w
microemulsion at low temperature to a w/o microemulsion at high temperature
(transitional phase inversion). During cooling, the system crosses a point of
zero spontaneous curvature and minimal surface tension, promoting the formation
of finely dispersed oil droplets. This method is referred to as phase inversion
temperature (PIT) method. Instead of the temperature, other parameter such as
salt concentration or pH value may be considered as well instead of the
temperature alone. Additionally, a transition in the spontaneous radius of
curvature can be obtained by changing the water volume fraction. By
successively adding water into oil, initially water droplets are formed in a
continuous oil phase. Increasing the water volume fraction changes the
spontaneous curvature of the surfactant from initially stabilizing a w/o
microemulsion to an o/w microemulsion at the inversion locus. Short-chain
surfactant form flexible monolayers at the o/w interface resulting in a
bicontineous microemulsion at the inversion point.
Method of preparation of microemulsion
based gel:
STEP 1:
Formulation of microemulsion either O/W or W/O.
STEP 2:
Formulation of gel base.
STEP 3: Incorporation of microemulsion into gel
base with continuous stirring.
Figure
2: Flow chart for preparation of microemulsion based gel
Characterization of microemulsion based
gel:[1-5]
1. Physical appearance:
The prepared microemulsion based gel
formulations were inspected visually for their color, consistency and phase
separation.
2. Compatibility studies by FTIR:
Compatibility study of drug with the
excipients was determined by FTIR Spectroscopy. Sample preparation involved
mixing the sample with potassium bromide, triturating in glass mortar and
finally placing in the sample holder. IR spectra of pure drug, drug-oil phase,
drug-surfactant, drug-co-surfactant, were taken. By this analysis, it was clear
that there were no changes in the main peaks of drug in IR spectra, conforming
no physical interactions between the excipients and the drug. If any changes,
IR spectra conclude that any interaction.
3. pH Determination:
A 10% dispersion of formulation was
prepared in distilled water and pH was determined using pH meter which was
prior standardized with standard buffers of pH 4 and pH 7.
4. Rheological studies:
The viscosity of the different
microemulsion based gel formulations is determined at 25 °C using a cone and
plate viscometer with spindle 52, and connected to a thermostatically controlled
circulating water bath.
5. Globule Size and its distribution in
microemulsion gel:
The average globule size of the
microemulsion was determined in triplicate by Zetasizer Nano ZS. Measurements
were carried at an angle of 90º at 25 ºC. Microemulsion was diluted with double
distilled water to ensure that the light scattering intensity was within the
instrument’s sensitivity range. All the measurement was carried out at 25 ºC.
6. Extrudability study of topical
microemulsion based gel:
It is usual empirical test to measure the
force required to extrude the material from the tube. The method adopted for
evaluating microemulsion based gel formulation for extrudability. And it is
based upon the quantity in percentage of gel and gel extruded from aluminium collapsible
tube on application of weight in grams required to extrude at least 0.5 cm
ribbon of microemulsion based gel in 10 seconds. More quantity extruded better
is extrudability. The measurement of extrudability of each formulation is in
triplicate and the average values are presented. The extrudability is then
calculated by using the following formula:
Extrudability (gm/cm2) = (Applied
weight to extrude microemulsion based gel from the tube)/Area
7. Spreadability:
The spreading co-efficient (Spreadability)
of the formulations was determined using an apparatus described by Jain et al.
The apparatus consisted of two glass slides (7.5 × 2.5 cm), one of which was
fixed onto the wooden board and the other was movable, tied to a thread which passed
over a pulley, carrying a weight. Formulation (1 g) was placed between
the two glass slides. Weight (100 g) was allowed to rest on the upper
slide for 1 to 2 minutes to expel the entrapped air between the slides and to
provide a uniform film of the formulation. The weight was removed, and the top
slide was subjected to a pull obtained by attaching 30 g weight over the
pulley. The time (sec) required for moving slide to travel a premarked distance
(6.5 cm) was noted and expressed as spreadability. Spreadability is
calculated by using the following formula:
Where, M = weight tied to upper slide
L = length of glass slides
T = time taken to separate the slides
Figure 3: Spreadability Apparatus
8. Swelling index:
To determine the swelling index of prepared
topical microemulsion based gel, 1 gm of gel is taken on porous aluminum foil
and then placed separately in a 50 ml beaker containing 10 ml 0.1 N NaOH. Then
samples were removed from beakers at different time intervals and put it in a
dry place for some time after it reweighed. Swelling index is calculated as
follows:
Swelling index (SW) % = 
Where,
(SW) % = Equilibrium percent swelling
Wt = Weight of swollen microemulsion based
gel after time t
Wo = Original weight of microemulsion based
gel at zero time
9. Drug content determination:
Take 1 gm of microemulsion based gel and
mix it in a suitable solvent. Filter it to obtain clear solution. Determine its
absorbance by using UV-Visible spectrophotometer. Standard plot of drug is
prepared in the same solvent. Concentration and drug content can be determined
by using the same standard plot by putting the value of absorbance. Drug
content calculated as given formula:
Drug Content = Concentration ×
Dilution Factor × Volume taken × Conversion Factor
10. Skin irritation test:
The skin irritation study was conducted in
accordance with the approval of the Animal Ethical Committee, using white male
rabbits (n=3) as test animals. The hair of rabbits on dorsal side was shaved
with electrical shaver and about 4 gm sample of the test article was then
applied to each site (two site per rabbit) by introduction under a double gauze
layer to an area of skin approximately 1” × 1” (2.54 × 2.54 cm2).
The gellified emulsion is applied on the skin of rabbits. The animals were
returned to their cages. After 24 hour exposure, the gellified emulsion is
removed. The test sites were wiped with tap water to remove any residual gel.
The development of erythema/edema was monitored for 3 days by visual
observation.
11. Ex-vivo bioadhesive strength
measurement of topical microemulsion gel:
(Mice shaven skin): The modified method is
used for the measurement of bioadhesive strength. The fresh skin is cut into
pieces and washed with 0.1 N NaOH. Two pieces of skin were tied to the two
glass slides separately from that one glass slide is fixed on the wooden piece
and another piece is tied with the balance on right hand side. The right and
left pans were balanced by adding extra weight on the left-hand pan. 1 gm of
topical microemulsion based gel is placed between these two slides containing
hairless skin pieces, and extra weight from the left pan is removed to sandwich
the two pieces of skin and some pressure is applied to remove the presence of
air. The balance is kept in this position for 5 minutes. Weight is added slowly
at 200 mg/min to the left-hand pan until the patch detached from the skin
surface. The weight (gram force) required to detach the microemulsion based gel
from the skin surface gave the measure of bioadhesive strength. The bioadhesive
strength is calculated by using the following formula:
Weight required
Bioadhesive Strength (gm/cm2) = ---------------------
Area
12. In-vitro release/permeation studies:
The in-vitro permeation rates of prepared
microemulsion based gel were determined to evaluate the effects of the
formulation factors. The diffusion experiments were performed using Franz
diffusion cells fabricated locally with dialysis membrane pore size: 0.2 mm at
37 ± 0.1 °C. The beaker was filled with 200 ml of phosphate buffer pH 7.4 which
acts as receptor fluid. The receptor fluid was constantly stirred by externally
driven magnetic beads. Accurately 1 gm of microemulsion based gel was placed in
the cylindrical hollow tube one end of which sealed by dialysis membrane pore
size: 0.2 mm. It acts as donor compartment. The aliquots 10 ml were collected
at suitable time intervals of 30 min up to 6 h. An equal volume of the fresh
phosphate buffer was immediately replenished after each sampling. The sample
was analyzed by UV-Visible spectrophotometer at a suitable wavelength after
appropriate dilutions with suitable solvent. Cumulative corrections were made
to obtain the total amount of drug release at each time interval.
13. Microbiological assay:
Ditch plate technique was used. It is a
technique used for evaluation of bacteriostatic or fungistatic acivity of a
compound. It is mainly applied for semisolid formulations. Previously prepared
Sabouraud’s agar dried plates were used. Three grams of the gellified emulsion
are placed in a ditch cut in the plate. Freshly prepared culture loops are
streaked across the agar at a right angle from the ditch to the edge of the
plate. After incubation for 18 to 24 hours at 25ºC, the fungal growth was
observed and the percentage inhibition was measured as follows:
% Inhibition =
Where;
L1 = total length of the streaked culture
L2= length of inhibition
14. Accelerated stability studies of
gellified emulsion:
Stability studies were performed according
to ICH guidelines. The formulations were stored in hot air oven at 37 ± 2 ºC,
45 ± 2 ºC and 60 ± 2 ºC for a period of 3 months. The samples were analyzed for
drug content every two weeks by UV-Visible spectrophotometer. Stability study
was carried out by measuring the change in pH of gel at regular interval of
time [22].
Table.2 Reported
examples of microemulsion based gel:[25-28]
|
Drug
|
Category
|
Gelling
agent
|
Reference
|
|
Bifanazole
|
Antifungal
|
HPMC
|
Sabale
and Vora (2012)
|
|
Itraconazole
|
Antifungal
|
Xanthangum,
Carbopol 940
|
Lee
et.a1. (2010)
|
|
Tretioin
|
Vitamin
A
|
Carbomer
934
|
Suthar
et.al.(2009)
|
|
Ibuprofen
|
NSAID
|
Xanthan
gum
|
Chen
et.al (2006)
|
Table.3Patentable formulations:[29-34]
|
Sr. No.
|
Patent No.
|
Formulation
|
|
1
|
US20140275263
A1
|
Microemulsion
Topical Delivery Platform
|
|
2
|
US5336432 A
|
Composition
for microemulsion gel having bleaching and antiseptic properties
|
|
3
|
EP 0760651 B1
|
Pharmaceutical
compositions derived from microelmulsion-based gels, method for their
preparation and new microemulsion-based gels
|
|
4
|
CN101933902 A
|
Granisetron
hydrochloride microemulsion-based gel and preparation method thereof
|
|
5
|
CN102423293 B
|
Microemulsion
gel preparation of oxiconazole nitrate
|
|
6
|
US20030083314
A1
|
Gel-microemulsion
formulations
|
CONCLUSION:
Microemulsion based gel system have proven
as most convenient, better and effective topical delivery system. Nowadays gels
are getting more popular because they are more stable and also can provide
controlled release. Due to its non-greasy gel like property and lacks of oily
bases it provides a better release of drugs as compared to other topical drug
delivery system. Incorporation of microemulsion into gel makes it a dual
controlled release system further problem such as phase separation, creaming
associated with microemulsion gets resolved and its stability can improve.
Microemulsion based gel loaded with specific drugs has been found effective in
some topical disorders such as fungal and arthritis disorders and it is
emerging as a potential drug delivery system.
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