NANOEMULGEL: A NOVEL FORMULATION APPROACH FOR … · rectal, vaginal, ophthalmic and skin as...

www.wjpps.com Vol 4, Issue 10, 2015. 1871

Basera et al. World Journal of Pharmacy and Pharmaceutical Sciences

NANOEMULGEL: A NOVEL FORMULATION APPROACH FOR

TOPICAL DELIVEREY OF HYDROPHOBIC DRUGS

Kalpana Basera*, Ganesh Bhatt, Preeti Kothiyal and Pooja Gupta

Department of Pharmaceutics Shri Guru Ram Rai Institute of Technology & Sciences

Dehradun, (248001) Uttrakhand, India.

ABSTRACT

The advances in knowledge about production and stability of dispersed

systems enable the development of differentiated vehicles such as

nanoemulsion and nanoemulgel. Dermatological products applied to

skin are diverse in formulation and range in consistency from liquids to

powder but the most popular products are semisolid preparations

.Topical gel are transparent or translucent semisolid formulation and

used for the localized drug delivery anywhere in the body through

rectal, vaginal, ophthalmic and skin as topical route. Gel formulation

provides better application property and stability in comparision of

ointment and cream. Nanoemulgel has emerged as one of the most

interesting topical delivery system as it has dual release control system

i.e. Hydrogel and nanoemulsion. Nanoemulgel having nanosize (10

-100µm) rapidly penetrates and deliver active substance deeper and quicker. The use of

emulgels can be considered well in analgesics and antifungal drugs. In recent year there has

been great interest in the use of novel polymer with complex function such as emulsifiers and

thickeners. The gelling capacity of this compound allows the formulation of stable emulsion

and creams by decreasing surface and interfacial tension at the same time increasing the

viscosity of aqueous phase. In spite of many advantage of gels a major limitation is in the

delivery of hydrophobic drug. So to overcome this limitation an emulsion based approach is

being used to that even a hydrophobic moiety can enjoy the unique property of gel.

KEYWORDS: Nanoemulgel, Nanoemulsion, Hydrogel, Skin, Hydrophobic Drugs.

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 5.210

Volume 4, Issue 10, 1871-1886 Research Article ISSN 2278 – 4357

Article Received on

14 Aug 2015,

Revised on 08 Sep 2015,

Accepted on 29 Sep 2015

*Correspondence for

Author

Kalpana Basera

Department of

Pharmaceutics Shri Guru

Ram Rai Institute of

Technology & Sciences

Dehradun, (248001)

Uttrakhand, India.



INTRODUCTION

The technological application of nanoemulsions have increasingly been used in various

application due to their characteristic properties, small droplet size, high interfacial area

,transparent or translucent appearance, high solubilization capacity, flocculation and in some

cases ,the coalescence.[1-3]

Nanoemulsions are novel drug delivery system consisting of

emulsified oil and water systems with mean droplet diameters ranging from 50 to 1000 nm.

Usually the average droplet size is between 100 and 500 nm and can exist as oil-in-water

(o/w) or water- in- oil(w/o) form, where the core particle is either oil or water, respectively.[4]

Nanoemulsions also have attracted a great attention in delivery of therapeutically active

agents since approximately 40% of new chemical entities are hydrophobic in nature and the

delivery of these poorly water soluble drugs is a challenge for delivery of drugs. In

pharmaceutical field , nanoemulsions have been used as a drug delivery system through

various systemic routes i.e oral, topical and parenteral. The emulsion and nanoemulsion differ

mainly in size and shape of the particle dispersed in the continuous phase.[5, 6]

Nanoemulgel which is also known as the formation of nanoemulsion-based hydrogel in the

addition of nanoemulsion system into the hydrogel matrix.[7-9]

The mixture of emulgel has

been the attention of many scientists for the development of numerous drugs that function to

treat various kind of skin disorders.[10, 11]

Combining nanoemulsion with hydrogel in forming

nanoemulgel with hydrogel in forming nanoemulgel has further improved the topical



formulation of nanoemulsion. With the gelling agent, it promotes better stability of

nanoemulsion by reducing the surface and interfacial tension and also enhancing viscosity of

the aqueous phase for drug administration topically.[12,13]

Drug delivered through

nanoemulgel has better adhesion on the surface on the surface of the skin and high

solubilizing capacity which leads to larger concentration gradient towards the skin, hence

influences better skin penetration.[14, 15, 16]

In addition, with the gel based formulation of

nanoemulgel, it exhibit upgraded properties of thixotropic, non greasy, effortlessly

spreadable, easily be removed and longer shelf life.[12]

Physiology of Skin

The skin is the largest organ of the body, accounting for about 15% of the total adult body

weight. It performs many vital functions. [17]

Protection against physical, chemical and biological assailants.

Prevention of excess water loss from the body.

Vital role in thermoregulation.

The skin consists of three layers i.e. the epidermis, the dermis and the subcutaneous tissue.

An average human skin surface is known to contain, on the average 40-70 hair follicles and

200-300 sweat ducts on every cm² of the skin. The pH of the skin varies from 4-5.6 the skin

of an average adult body covers a surface area approximately 2m² and receives about one

third of the blood circulating through the body.

Advantages of Emulgel

Avoidance of systemic adverse effects of drug i.e. first pass metabolism in the body.

Systemic circulation is minimized or prevented.

Improve patient compliance and acceptability.

Suitable for self-medication.

Provide target drug delivery on the body.

Ability to easily terminate medication.

Can easily pass through skin having dual behavior i.e. hydrophobic as well as

hydrophilic.

They are convenient to apply on hairy skin due to absence of greasiness and lack of

residues upon application.



Disadvantages of NanoEmulgel

Skin irritation on contact dermatitis.

Bubbles formed during emulgel formulation.

Possibility of allergenic reactions.

Drugs having large particle size (>400 daltons) are not easily absorb or cross through the

skin barrier.

The Epidermis

This is a stratified squamous epithelium layer i.e. composed primarily of two types of cells:

keratimocytes and dendritic cells. Epidermis layer harbour a number of other cells such as

melanocytes, Langerhans cells and Merkel cells. But the keratimocytes cells types comprises

the majority of the cells by far. The layers of epithelium are –

Stratum germinativum (growing layer or basal layer): It contains column-shaped

keratimocytes that attach to the basement membrane zone with their long-axis

perpendicular to dermis.

Stratum spinosum (prickly cell layer or squamous cell layer) : Its thickness varies from 5-

10 cells. Intercellular spaces between spinous cells are bridged by abundant

Desmosomes (adhering spot) that promote coupling between cells of the epidermis and

provide resistance to physical stresses.



Stratum granulosum (granular layer): It contains living cells, these are responsible for

further synthesis and modification of proteins involved in keratinization. It is 1-3 cells

layer in thickness.

Stratum corneum (horny layer): the conrneocytes are rich in protein and low in lipid

content (hydrophilic nature) are surrounded by a continuous extracellular lipid matrix.

Malpighian layer (pigment layer): the layer whose protoplasm has not yet change into

horny material.

Stratum lucidium

The Dermal-Epidermal

It act as a support for the epidermis, establishes cell polarity and direction of growth, directs

the organization of the cytoskeleton in basal cells, provide developmental signals and

function as a semi-permeable barrier between layer.

The Dermis

It is on integrated system of fibrous, filamentous and amorphous connective tissue that

accommodates stimulus induced entry by nerve, vascular-networks, appendages, fibroblasts,

mast cells. Its thickness ranges from 2000-3000μm. The principal component of the dermis is

collagen and represents 70% of the skin’s dry weight.

Sub-cutaneous (Connective Tissue)

The subcutaneous tissue or hypodermis is not actually considered a true part of the structured

connective tissue which is composed of loose textured, white, fibrous connective tissue

containing blood and lymph vessels, secretary pores of the sweat gland and cutaneous nerves.

Most investigators consider drug permeating through the skin enter the circulatory system

before reaching the hypodermis, although the fatty tissue could serve as a depot of the drug.

Factors Affecting Topical Absorption of Drug11

Physiological Factors

1. Skin thickness – varies from epidermis to subcutaneous layer. Epidermis has high

thickness about 100-150μm. Skin on the sole and palm has a high rate of diffusion.

2. Lipid content - it is an effective water barrier, percutaneous penetration increases when

lipid weight in stratum corneum is low.

3. Density of hair follicles – hair follicle in fundibulum has a large storage capacity about 10

times more than the stratum corneum.



4. Density of sweat glands

5. Skin pH – sweat and fatty acid secreted from sebum influence the pH of the skin surface.

6. Hydration of skin – can enhance permeation of drug.

7. Inflammation of skin – that disrupts the continuity of stratum corneum increases

permeability.

8. Skin temperature – increase in temperature gives rise to increase in rate of skin permeation.

9. Blood flow

Physicochemical Factors

1. Partition coefficient – more the value of log p more easily will be the percutaneous

absorption of the drug.

2. Molecular weight (< 400 Dalton)

3. Degree of ionization – only unionized drug molecules get absorbed well.

4. Effect of vehicles – hydro alcoholic gel provides the most efficient absorption through

skin.

Advantages of using Emulgel as a Drug Delivery System[29]

Hydrophobic drugs can be easily incorporated into gels using d/o/w emulsions

Most of the hydrophobic drugs cannot be incorporated directly into gel base because

solubility act as a barrier and problem arises during the release of the drug. Emulgel 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.

Better stability

Other transdermal preparations are comparatively less stable than emulgels. Like powders are

hygroscopic, creams shows phase inversion or breaking and ointment shows rancidity due to

oily base.

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.



Production feasibility and low preparation cost

Preparation of emulgels comprises of simpler and short steps which increases the feasibility

of the production. There are no specialized instruments needed for the production of

emulgels. Moreover materials used are easily available and cheaper. Hence, decreases the

production cost of emulgels.

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 emulgels as no

sonication is needed.

Controlled release

Emulgels can be used to prolong the effect of drugs having shorter t½.

Patient compliance

They are less greasy and easy to apply.

Classification of Topical Drug Delivery System

METHODS

Generally there are several steps involved in formulation of nanoemulgel, which can be

summarized in three steps, first formulation of nanoemulsion. Second formulation of



hydrogel using thickening agent, which increase the consistency of any dosage form. Finally

nanoemulgel is prepared by the incorporation of nanoemulsion into hydrogel.

Formulation of nanoemulsion

Nanoemulsion is prepared by using methods i.e. phase inversion technique and self

emulsifying system. Formations of pre-nanoemulsion mixtures are required before they could

be self-emulsified in water under gentle, to produce nanoemulsion at room temperature.

A series of mixture of combination of oil phase, surfactant and co-surfactant are prepared to

produce nano emulsion. A pseudoternary phase diagram is constructed based on the oil,

surfactant and co-surfactant at a constant temperature to produce nanoemulsion. For each

phase diagram, oil and specific Smix (surfactant and co surfactant) ratio were mixed

thoroughly in different volume ratios in different glass vials. The Smix ratios are selected to

reflect increasing concentrations of co surfactant with respect to surfactant for detailed study

of the phase diagrams in the nanoemulsion formulation. Slow titration with the aqueous phase

is performed for each combination of oil and Smix separately. For each Smix ratios, a

separate phase diagram is constructed. Pseudoternary phase diagram with first axis

representing the aqueous phase, second representing the oil phase and third representing a

mixture of surfactant and co surfactant at a fixed volume ratio are constructed. Hence the

various formulations of nanoemulsions are produced by pseudoternary phase diagram.



Optimization of nanoemulsion

Morphology and structure of nanoemulsion

The morphology of nanoemulsions can be determined by transmission electron microscopy

(TEM) and scanning electron microscopy (SEM). SEM gives a three dimensional image of

the globules. The samples are examined at suitable accelerating voltage, usually 20 kV, at

different magnifications. A good analysis of surface morphology of disperse phase in the

formulation is obtained through SEM. Image analysis software may be employed to obtain an

automatic analysis result of the shape and surface morphology. In TEM, higher resolution

images of the disperse phase are obtained. The sample is negatively stained with 1% aqueous

solution of phosphotungstic acid or by dropping 2 % uranyl acetate solution onto a 200 μm

mesh size Pioloform™- coated copper grid or a microscopic carbon-coated grid using a

micropipette and the sample examined under a transmission electron microscope at

appropriate voltage. Qualitative measurements of sizes and size distribution of TEM

micrographs can be performed using a digital image processing programme. More

sophisticated techniques, such as x-ray or neutron scattering, atomic force microscopy, or

cryo-electron microscopy are typically required to explore the structure and behaviour of

nanoemulsions].

Droplet size , polydispersity and zeta potential of Nanoemulsions

Dynamic light scattering (DLS) otherwise called photon correlation spectroscopy (PCS) is

used to analyze the fluctuations in the intensity of scattering by droplets/particles due to

Brownian motion.[18]

Nanoemulsion droplet size, polydispersity and zeta potential can be

assessed by PCS using a particle size analyzer. This instrument also measures polydispersity

index, which is a measure of the broadness of the size distribution derived from the

cumulative analysis of dynamic light scattering. The polydispersity index indicates the

quality or homogeneity of the dispersion.[19]

PCS gives z-average particle diameter. Laser

diffraction is another technique for measuring particle size. The fundamental particle size

distribution derived by this technique is volume based and is expressed in terms of the

volume of equivalent spheres (DN%) and weighted mean of the volume distribution (mass

mean diameter). Since the laser diffraction system is used for this analysis, a rough equivalent

of particle polydispersity could be given by two factors/values namely, uniformity (how

symmetrical the distribution is around the median point) and span (the width of the

distribution).



The span value is defined by the expression.

Span = (D90%- D10%) / D50% (2)

Where DN% (N=10%, 50%, 90%), means that the volume percentage of particles with

diameters up to DN% equals to N%. The smaller the span value the narrower the particle size

distribution.

Viscosity of nanoemulsion

This is carried out using a viscometer. The viscosity of nanoemulsions is a function of the

surfactant, water and oil components and their concentrations. Increasing the water content

lowers the viscosity, while decreasing the amount of surfactant and co surfactant increases

interfacial tension between water and oil resulting in increased viscosity. Viscosity is very

important for stability and efficient drug release. Nanoemulsion carrier formulations are

basically oil-in-water and so in addition to being less greasy than water-in-oil formulations,

often possess lower apparent viscosities. They are therefore expected to exhibit faster release

of active ingredients and wash out easily after application on the skin surface. Various

equipment and methods are available for assessment of rheological properties of

nanoemulsion carriers. Monitoring of viscosity change is a method of assessing stability of

liquid and semi-solid preparations including nanoemulsion formulations.[20]

Formulation of nanoemulgel

All the formulations (B1-B9) were found in nano size range and therefore incorporated in the

gel matrix resulting in nanoemulgel. Carbomer 934 was selected as gel matrix base. The oily

phase was obtained by mixing oleic acid, tween 80, ethanol and drug. Carbomer 934 was

swelled in a little water for 24 h and a high viscous solution was obtained and then the oily

phase was slowly added to the viscous solution of Carbomer 934 under magnetic stirring.



The pH values were subsequently regulated to 6-9 by using triethanolamine and nanoemulgel

was obtained. The concentration of Carbomer 934 in nanoemulgel was 0.5% (w/w).[22]

Characterization of nanoemulgel

Drug content determination

The amount of drug contained in the prepared nanoemulgel was determined by diluting

required amount of prepared formulation using phosphate buffered saline (PBS) 7.4. This

mixture was analyzed by UV spectrophotometer at 240 nm against PBS 7.4 as blank.[22]

pH determination

Since the formulation was a topical formulation to be applied to the skin, therefore pH

measurement was essential to ensure non irritating nature of the formulation. The pH of the

formulation was determined at ambient temperature with digital pH meter (Rolex, India).

Spreadability

The Spreadability of prepared nanoemulgel was determined 48 h after preparation by

measuring the spreading diameter of nanoemulgel between the two glass plates after 1 min. A

weight of 350 mg of nanoemulgel was placed within a circle of diameter 1 cm pre-marked on

the glass plate over which a second glass plate was placed. The increase in diameter as a

consequence of weights added leading to spreading of gel was noted. The Spreadability can

be calculated by using the formula (2)

Where, S = Spreadability, m = Weight placed on upper slide,

l = Length of upper slide and t = The time taken.

Viscosity measurements and rheological behavior

A Brookfield LVT DV-II Programmable Viscometer of Engineering Laboratories, Inc.,

(Middleboro, MA, USA) was connected to a thermostatic water bath adjusted to 25°C.

Viscosity was measured on each base by using spindle 40. A defined amount (1 g) of each gel

base was placed inside the plate and carefully closed. The measurement was started by

operating the viscometer at 0.6 rpm, the speed was gradually increased and the measurement

was recorded when the torque reached 10%. The speed was gradually increased at a constant

rate for all tested samples until the torque reached 90%, with 30 s between each successive

speed. The rheological parameters, including viscosity, shear rate, shear stress and yield

value, were directly obtained from the monitor. The speed was then reduced gradually, using

the same order as the increasing speeds, until reaching the starting rpm. A complete rheogram



was obtained by plotting the shear rate as a function of the shear stress.[23]

For pseudoplastic

flow, the exponential formula has been used most frequently.

η’ = (FN)/G (3)

The exponent N (Farrow’s constant) rises as the flow becomes increasingly non-Newtonian.

The term η’ represents viscosity coefficient. By the arrangement of the above equation,

log G = N log F – log η’ (4)

An equation for a straight line is obtained. Many pseudoplastic systems fit this equation when

log G is plotted as a function of log F.

Ex vivo drug permeation studies

The ex vivo permeation studies were carried out using Franz diffusion cell, which is a reliable

method for prediction of drug transport across the skin. [24]

These studies were conducted

employing excised skin of Wistar rats. The hair on the dorsal side of the sacrificed animal

was removed with a surgical blade no. 24 in the direction of tail to head. The shaven part of

the animal skin was separated, excess fat and connective tissue were removed using scalpel.

The excised skin was washed with normal saline, examined for integrity and subsequently

used. The receptor compartment of the diffusion cell was filled with 20 mL phosphate buffer

pH 7.4. The whole assembly was fixed on a magnetic stirrer and the solution in the receptor

compartment was constantly and continuously stirred using magnetic beads at 100 rpm and

the temperature was maintained at 37 ± 0.50°C throughout the experiments. The skin was

mounted on diffusion cell assembly with an effective diffusion area (orifice area) of 4.91

cm2. The prepared formulation (1 g) was applied onto the membrane in donor compartment.

An aliquot of 2 mL sample was withdrawn at a suitable time intervals and replaced

immediately with an equal volume of fresh diffusion medium. Samples were analyzed

spectrophotometrically. The drug permeated per cm2 of membrane was calculated and

plotted against time and the flux was calculated as drug permeated per cm2/h.

Comparison of permeation studies of marketed

Formulation, optimized nanoemulgel, nanoemulsion, plain drug gel and drug solution. The ex

vivo permeation study of optimized nanoemulgel formulation (BG6) was compared with the

marketed formulation (Feldene®, Pfizer Ltd., Mumbai, India) for permeation and retention

characteristics. The cumulative amount of drug permeated through the skin per unit area was

plotted as a function of time. The permeation rate of drug at steady state (Jss mg/cm/h)

through skin was calculated from the slope of the linear portion of plotted curve. The lag time



(Tlag) was determined by extrapolating the linear portion of the cumulative amount

permeated versus time curve to the abscissa. Enhancement ratio (Epen) was calculated by

dividing Jss of respective formulation with Jss of control formulation. [25]

The amount of piroxicam retained in the skin was determined at the end of the experiment.

Skin was removed where effective permeation of skin was cut, washed 3 times with saline

solution and washed off. The sample of skin was homogenized in 1 mL methanol. Resulting

solution was centrifuged at 3000 rpm for 10 min and analyzed for retention. Local

accumulation efficiency (LAE) was obtained as the ratio of drug accumulated in the skin to

that delivered through the skin. [26, 27]

Release kinetics

To study the release kinetics, data obtained from ex vivo permeation studies were fitted in

various kinetic models: Zero order as cumulative percent of drug released versus time, first

order as log cumulative percentage of drug remaining versus time and Higuchi’s model as

cumulative percent drug released versus square root of time. To determine the mechanism of

drug release, the data were fitted into Korsmeyer and Peppas equation as log cumulative

percentage of drug released versus log time and the exponent n was calculated from the slope

of the straight line. For slab matrix, if the exponent is 0.5, then diffusion mechanism is

fickian; if 0.5 < n < 1.0, mechanism is non-fickian.

Stability studies

Thermodynamic stability studies Nano emulsions are thermodynamically stable system and

are formed at a particular concentration of oil, mixture of surfactant and co-surfactant and

water, with no phase separation, creaming and cracking. Thermodynamic stability of

prepared nanoemulgel formulation was assessed by stability under centrifugation and

freeze/thaw cycles. [28]

The stability under centrifugation reflects the strength of interfacial film. The nanoemulgel

formulation was centrifuged at 3500 rpm for 30 min. In the case with freeze/thaw cycles, Test

tubes filled with the nanoemulgel were hermetically sealed and vertically stored for 16 h in a

freezer at −21°C and then for 8 h at room temperature (25°C). The nanoemulgel was

observed for any change. This cycle was repeated 3 times.



Stability studies at different temperature conditions

Temperature stress studies were conducted by storing the formulation at different temperature

conditions. Each formulation was stored in sealed glass containers in refrigerator (4°C), at

ambient temperature (25°C) and at accelerated temperature (40°C) for 90 days. After 1, 7, 14,

21, 30, 45, 60 and 90 days, the formulations were evaluated for any physical change (such as

clarity, phase separation, precipitation of drug, color change), drug content and pH.[28]

Statistical analysis

All experimental measurements were performed in triplicates. Result values were expressed

as the mean value ± standard deviation. Statistical analysis of difference in steady state flux

and ex vivo permeation among predetermined intervals between formulations was performed

by using unpaired t-test. The level of significance was taken at P < 0.05.

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