MICROEMULSION AS A CARRIER FOR NOSE TO BRAIN TARGETING… · MICROEMULSION AS A CARRIER FOR NOSE TO BRAIN TARGETING: ... 1Dept. of Pharmacy, ... because of its improved drug solubilization

Vol-2, Issue-2, Suppl-1 ISSN: 0976-7908 Dhakar et al

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PHARMA SCIENCE MONITOR AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES

MICROEMULSION AS A CARRIER FOR NOSE TO BRAIN TARGETING: A REVIEW AND UPDATE

Ram Chand Dhakar1*, Sheo Datta Maurya1, Anish K Gupta2, Anurag Jain1,

Sanwarmal Kiroriwal3,4, Manisha Gupta3

1Dept. of Pharmacy, IEC College of Eng & Technology, Gr Noida INDIA-201308 2Amarnath Pharmaceuticals, Pandicheri, INDIA-605001 3HIMT College of Pharmacy, Gr Noida, INDIA-201308 4NIPER and IICT - Hyderabad, INDIA -500007

ABSTRACT There are various approaches in delivering a therapeutic substance to the target site in a controlled release fashion. One such approach is using microemulsion as carriers for drugs. Recently, there has been a considerable interest for the microemulsion formulation, for the delivery of hydrophilic as well as lipophilic drug as drug carriers because of its improved drug solubilization capacity, long shelf life, easy of preparation and improvement of bioavailability. Microemulsion is the reliable means to deliver the drug to the target site with specificity, if modified, and to maintain the desired concentration at the site of interest without untoward effects. Microemulsion received much attention not only for prolonged release, but also for targeting of drugs to a particular site. The intent of the paper is focuses on use of microemulsion technology in drug targeting to the brain along with mechanism of nose to brain transport, formulation and formation of microemulsion and its characterization. Key words: Controlled release, Microemulsion, Drug carrier, Target site, Nose to Brain transport INTRODUCTION

The selection of an appropriate dosage form is critical because a dosage form with

poor drug delivery can make a useful drug worthless. Bioavailability has important

clinical implications as both pharmacologic and toxic effects are proportional to both

dose and bioavailability[1].

Many approaches have been meticulously explored to brain targeting of such

drugs i.e. Nanoparticles, liposomes; but these methods are not always practical. For

example, Nanoparticles are difficult to prepare and their preparation requires an

additional step in order to attach or loading the drug to the particles. Also the prepared



Nanoparticles show often shows a wide size distribution, as opposed to microemulsion,

which is monodispersed. Another disadvantage is the limited solubility of drug in the

Nanoparticles. Finally the polymer generally used in Nanoparticles are not usually

biocompatible, thus toxicity is another problem[2].

Of late lipid-based formulations have attracted great deal of attention in Drug

targeting and to improve the oral bioavailability of poorly water soluble drugs. In fact, the

most favored approach is to incorporate lipophilic drugs into inert lipid vehicles such as

oils, surfactant dispersions, microemulsions, self-emulsifying formulations and self

microemulsifying formulations[3-6].

Microemulsions are liquid dispersions of water and oil that are made

homogenous, transparent or translucent and thermodynamically stable by the addition of

relatively large amounts of a surfactant and a co-surfactant and having diameter of the

droplets in the range of 10 – 100 nm[7, 8, 9-11]. Microemulsions have been widely studied

for drug targeting to the brain and to enhance the bioavailability of the poorly soluble

drugs[12]. They offer a cost effective approach in such cases. Microemulsions have very

low surface tension and small droplet size which results in high absorption and

permeation. Interest in these versatile carriers is increasing and their applications have

been diversified to various administration routes in addition to the conventional oral

route. This can be attributed to their unique solubilization properties and thermodynamic

stability which has drawn attention for their use as carrier for drug targeting to the brain.

Intranasal drug delivery is one of the focused delivery options for brain targeting, as the

brain and nose compartments are connected to each other via the olfactory route and via

peripheral circulation.

Literature survey revealed that intranasal administration of microemulsion offers

a practical, noninvasive, alternative route of administration for drug delivery to the

brain[13,14]. Intranasal administration allows transport of drugs to the brain circumventing

BBB, thus providing better option to target drugs to the brain[15-19]. Therefore particularly

intranasal microemulsions are promising carrier for achieving the goals in drug targeting

to brain.

INTRANASAL DELIVERY FOR BRAIN TARGETING



Many drugs are not being effectively and efficiently delivered using conventional

drug delivery approach to brain due to its complexity. Intranasal drug delivery is one of

the focused delivery options for brain targeting, as the brain and nose compartments are

connected to each other via the olfactory route and via peripheral circulation. Realization

of nose-to-brain transport and the therapeutic viability of this route can be traced from the

ancient times and has been investigated for rapid and effective transport in the last tow

decades. The development of nasal drug products for brain targeting is still faced with

enormous challenges. A better understanding in terms of properties of the drug candidate,

nose-to-brain transport mechanism, and transport to and within the brain is of utmost

importance.

For some time the BBB has impeded the development of many potentially

interesting CNS drug candidates due to their poor distribution into the CNS. Owing to the

unique connection of the nose and the CNS, the intranasal route can deliver therapeutic

agents to the brain bypassing the BBB. Absorption of drug across the olfactory region of

the nose provides a unique feature and superior option to target drugs to brain. Many

scientists have reported evidence of nose-to-brain transport. Many previously abandoned

potent CNS drug candidates promise to become successful CNS therapeutic drugs via

intranasal delivery. Recently, several nasal formulations, such as ergotamine (Novartis),

sumatriptan (GlaxoSmithKline), and zolmitriptan (AstraZeneca) have been marketed to

treat migraine. Scientists have also focused their research toward intranasal

administration for drug delivery to the brain especially for the treatment of diseases, such

as epilepsy[15,20-24], migraine[13,14,18,25-27], emesis, depression[28], angina pectoris[29] and

erectile dysfunction[30].

MECHANISM OF NOSE TO BRAIN DRUG TRANSPORT

It is important to examine the pathway/mechanisms involved prior to addressing

the possibilities to improve transnasal uptake by the brain[31-33]. The olfactory region is

known to be the portal for a drug substance to enter from nose-to-brain following nasal

absorption. Thus, transport across the olfactory epithelium is the predominant concern for

brain targeted intranasal delivery. Nasal mucosa and subarachnoid space; lymphatic

plexus located in nasal mucosa and subarachnoid space along with perineural sheaths in

olfactory nerve filaments and subarachnoid space appears to have communications



between them. The nasal drug delivery to he CNS is thought to involve either an

intraneuronal or extraneuronal pathway[34, 35].

A drug can cross the olfactory path by one or more mechanism/pathways. These

include paracellular transport by movement of drug through interstitial space of cells

transcellular or simple diffusion across the membrane or receptor / fluid phase mediated

endocytosis and transcytosis by vesicle carrier [36] and neuronal transport. The

paracellular transport mechanism/route is slow and passive. It mainly uses an aqueous

mode of transport. Usually, the drug passes through the tight junctions and the open clefts

of the epithelial cells present in the nasal mucosa. There is an inverse log-log correlation

between intranasal absorption and the molecular weight of water soluble compounds.

Compounds, which are highly hydrophilic in nature and/or of low molecular weight, are

most appropriate for paracellular transport. A sharp reduction in absorption and poor

bioavailability was observed for the drugs having molecular weight greater than 1000 Da.

Moreover, drugs can also cross cell membranes by a carrier – mediated active transport

route. For example, chitosan, a natural biopolymer from shellfish, stretches and opens up

the tight junctions between epithelial cells to facilitate drug transport. The transcellular

transport mechanisms / pathways mainly encompass transport via a lipoidal route [37, 38].

The drug can be transported across the nasal mucosa/epithelium by either receptor

mediated endocytosis or passive diffusion or fluid phase endocytosis transcellular route.

Highly lipophilic drugs are expected to have rapid/complete transnasal uptake. The

olfactory neuron cells facilitate the drug transport principally to the olfactory bulb.

Figure 1 Nose to brain transport routes



ADVANTAGES OF INTRANASAL DRUG DELIVERY

Non – invasive, rapid and comfortable.

Bypasses the BBB and targets the CNS, reducing systemic exposure and thus

systemic exposure and thus systemic side effects.

Does not require nay modification of the therapeutic agent being delivered

neurological and psychiatric disorders.

Rich vasculature and highly permeable structure of the nasal mucosa greatly

enhance drug absorption.

Problem of degradation of peptide drugs in minimized up to a certain extent.

Easy accessibility to blood capillaries.

Avoid destruction in the gastrointestinal tract, hepatic first pass metabolism and

increased bioavailability.

LIMITATIONS OF INTRANASAL DRUG DELIVERY

Concentration achievable in different regions of the brain and spinal cord varies

with each agent.

Delivery is expected to decrease with increasing molecular weight of drug.

Some therapeutic agents may be susceptible to partial degradation in the nasal

mucosa or may cause irritation to the mucosa.

Nasal congestion due to cold or allergies may interfere with this method of

delivery.

Frequent use of this route may result in mucosal damage.

FACTORS AFFECTING BRAIN-TARGETED NASAL DELIVERY SYSTEMS

Some of the physicochemical, formulation and physiological factors are

imperative and must be considered prior to designing intranasal delivery for brain

targeting.

1. Physicochemical properties of drugs:

i) Chemical form: The chemical form of a drug is important in determining absorption.

For example, conversion of the drug into a salt or ester form can also alter its absorption.

Huang et al 1985 studied the effect of structural modification of drug on absorption[39]. It

was observed that in-situ nasal absorption of carboxylic acid esters of L-Tyrosine was

significantly greater than that of L-Tyrosine.



ii) Polymorphism: Polymorphism is known to affect the dissolution rate and solubility of

drugs and thus their absorption through biological membranes.

iii) Molecular Weight: A linear inverse correlation has been reported between the

absorption of drugs and molecular weight up to 300 Da. Absorption decreases

significantly if the molecular weight is greater than 1000 Da except with the use of

absorption enhancers. The apparent cut-off point for molecular weight is approximately

1,000 with molecules less than 1,000 having better absorption. Shape is also important.

Linear molecules have lower absorption than cyclic – shaped molecules.

iv) Particle Size: It has been reported that particle sizes greater than 10μm are deposited

in the nasal cavity. Particles that are 2 to 10 μm can be retained in the lungs and particles

of less than 1 μm are exhaled.

v) Solubility & dissolution Rate: Drug solubility and dissolution rates are important

factors in determining nasal absorption from powders and suspensions. The particles

deposited in the nasal cavity need to be dissolved prior to absorption. If a drug remains as

particles or is cleared away, no absorption occurs.

2. Formulation factors:

i) pH of the formulation: Both the pH of the nasal cavity and pKa of a particular drug

need to be considered to optimize systemic absorption. Nasal irritation is minimized

when products are delivered with a pH range of 4.5 to 6.5. Also, volume and

concentration are important to consider. The delivery volume is limited by the size of the

nasal cavity. An upper limit of 25 mg/dose and a volume of 25 to 200 μL/ nostril have

been suggested.

To avoid irritation of nasal mucosa;

To allow the drug to be available in unionized form for absorption;

To prevent growth of pathogenic bacteria in the nasal passage;

To maintain functionality of excipients such as preservatives; and

To sustain normal physiological ciliary movement.

Lysozyme is found in nasal secretions, which is responsible for destroying certain

bacteria at acidic pH. Under alkaline conditions, lysozyme is inactivated and the nasal

tissue is susceptible to microbial infection. It is therefore advisable to keep the



formulation at a pH of 4.5 to 6.5 keeping in mind the physicochemical properties of the

drug as drugs are absorbed in the unionized form.

ii) Buffer Capacity: Nasal formulations are generally administered in small volumes

ranging from 25 to 200μL. Hence, nasal secretions may alter the pH of the administrated

dose. This can affects the concentration of unionized drug available for absorption.

Therefore, an adequate formulation buffer capacity may be required to maintain the pH

in-situ.

iii) Osmolarity: Drug absorption can be affected by tonicity of formulation. Shrinkage of

epithelial cells has been observed in the presence of hypertonic solutions. Hypertonic

saline solutions also inhibit or cease ciliary activity. Low pH has a similar effect as that

of a hypertonic solution.

iv) Gelling / Viscosity building agents or gel-forming carriers: Pennington et al 1988

studied that increase in solution viscosity may provide a means of prolonging the

therapeutic effect of nasal preparations40. Suzuki et al 1999 showed that a drug carrier

such as hydroxypropyl cellulose was effective for improving the absorption of low

molecular weight drugs but did not produce the same effect for high molecular weight

peptides[41]. Use of a combination of carriers is often recommended from a safety (nasal

irritancy) point of view.

v) Solubilizers: Aqueous solubility of drug is always a limitation for nasal drug delivery

in solution. Conventional solvents or co-solvents such as glycols, small quantities of

alcohol, Transcutol (diethylene glycol monoethyl ether), medium chainnglycerides and

Labrasol can be used to enhance the solubility of drugs[42]. Other options include the use

of surfactants or cyclodextrins such as HP-β-cyclodextrin that serve as a biocompatible

solubilizer and stabilizer in combination with lipophilic absorption enhancers.

vi) Preservatives: Most nasal formulations are aqueous based and need preservatives to

prevent microbial growth. Parabens, benzalkonium chloride, phenyl ethyl alcohol, EDTA

and benzoyl alcohol are some of the commonly used preservatives in nasal formulations.

Van De Donk et al 1980 have shown that mercury containing preservatives have a fast

and irreversible effect on ciliary movement and should not be used in the nasal

systems[43].



vii) Antioxidants: Usually, antioxidants do not affect drug absorption or cause nasal

irritation. Chemical / physical interaction of antioxidants and preservatives with drugs,

excipients, manufacturing equipment and packaging components should be considered as

part of the formulation development program. Commonly used antioxidants are sodium

metabisulfite, sodium bisulfite, butylated hydroxyl toluene and tocopherol.

viii) Humectants: Many allergic and chronic diseases are often connected with crusts and

drying of mucous membrane. Adequate intranasal moisture is essential for preventing

dehydration. Therefore humectants can be added especially in gel-based nasal products.

Humectants avoid nasal irritation and are not likely to affect drug absorption. Common

examples include glycerin, sorbitol and mannitol.

ix) Drug Concentration, Dose & Dose Volume: Drug concentration, dose and volume of

administration are three interrelated parameters that impact the performance of the nasal

delivery performance. Nasal absorption of L-Tyrosine was shown to increase with drug

concentration in nasal perfusion experiments.

x) Role of Absorption Enhancers: Absorption enhancers may be required when a drug

exhibits poor membrane permeability, large molecular size, lack of lipophilicity and

enzymatic degradation by amino peptidases. Osmolarity and pH may accelerate the

enhancing effect. Examples of enhancing agents are surfactants, glycosides,

cyclodextrins, and glycols. Absorption enhancers improve absorption through many

different mechanisms, such as increasing membrane fluidity, increasing nasal blood flow,

decreasing mucus viscosity, and enzyme inhibition.

3. Physiological factors:

i) Effect of Deposition on Absorption: Deposition of the formulation in the anterior

portion of the nose provides a longer nasal residence time. The anterior portion of the

nose is an area of low permeability while posterior portion of the nose where the drug

permeability is generally higher, provides shorter residence time.

ii) Nasal blood flow: Nasal mucosal membrane is very rich in vasculature and plays a

vital role in the thermal regulation and humidification of the inhaled air. The blood flow

and therefore the drug absorption will depend upon the vasoconstriction and

vasodilatation of the blood vessels.



iii) Effect of Mucociliary Clearance: The absorption of drugs is influenced by the

residence (contact) time between the drug and the epithelial tissue. The mucociliary

clearance is inversely related to the residence time and therefore inversely proportional to

the absorption of drugs administered. A prolonged residence time in the nasal cavity may

also be achieved by using bioadhesive polymers or by increasing the viscosity of the

formulation.

iv) Effect of Enzymatic Activity: Several enzymes that are present in the nasal mucosa

might affect the stability of drugs. For example, proteins and peptides are subjected to

degradation by proteases and amino-peptidase at the mucosal membrane. The level of

amino-peptidase present is much lower than that in the gastrointestinal tract. Peptides

may also form complexes with immunoglobulin (Igs) in the nasal cavity leading to an

increase in the molecular weight and a reduction of permeability.

v) Effect of Pathological Condition: Intranasal pathologies such as allergic rhinitis,

infections, or pervious nasal surgery may affect the nasal mucociliary transport process

and/or capacity for nasal absorption. During the common cold, the efficiency of an

intranasal medication is often compromised. Nasal clearance is reduced in insulin-

dependent diabetes. Nasal pathology can also alter mucosal pH and thus affect absorption

of drugs.

MICROEMULSIONS AS INTRA NASAL DRUG DELIVERY

Microemulsions or micellar emulsions are defined as single optically isotropic

and thermodynamically stable multi component fluids composed of oil, water and

surfactant (usually in conjunction with a cosurfactant). The droplets in a microemulsion

are in the range of 1 nm-100 nm in diameter7-11. The basic difference between emulsions

and microemulsions is that emulsions exhibit excellent kinetic stability but they are

thermodynamically unstable as compared to microemulsions. In recent years

microemulsions have attracted a great deal of attention because of their biocompatibility,

biodegradability, ease of preparation and handling and most importantly solubilization

capacity for both water and oil soluble drugs[12,44].



Figure 2 O/W type, W/O type and Bicontinuous microemulsion

Microemulsions have various textures such as oil droplets in water, water droplets

in oil, bi continuous mixtures (Fig 2).

WHY MICROEMULSION IS PREFERS OVER THE OTHER DOSAGE FORMS

In recent years microemulsions have attracted a great deal of attention because of

their following advantages;

1. Ease of manufacturing and scale-up.

2. Wide applications in colloidal drug delivery systems for the purpose of drug

targeting and controlled release.

3. Helps in solubilization of lipophillic drug hence Increase the rate of absorption

and bioavailability of drugs[12].

4. Eliminates variability in absorption.

5. Provides a aqueous dosage form for water insoluble drugs.



6. Various routes like tropical, oral and intravenous can be used to deliver the

drugs[45].

7. Rapid and efficient penetration of the drug moiety.

8. Helpful in taste masking.

9. Same microemulsions can carry both lipophilic and hydrophilic drugs[46].

10. Provides protection from hydrolysis and oxidation as drug in oil phase in O/W

microemulsion is not exposed to attack by water and air.

11. Liquid dosage form increases patient compliance.

12. Less amount of energy requirement.

13. Microemulsion lower the skin irritation: alcohol-free microemulsions have been

reported with much lower irritation potential.

14. Long self life as compared to other colloidal drug delivery system.

15. High drug loading.

16. Improve therapeutic efficacy of drugs and allow reduction in the volume of the

drug delivery vehicle, thus minimizing toxic side effects[47].

17. Easy to administer in child and adults who have difficulty swallowing solid

dosage forms

WHY MICROEMULSIONS ARE CHOSEN FOR NOSE TO BRAIN DRUG

DELIVERY

Literature survey revealed that intranasal administration of microemulsion offers

a practical, noninvasive, alternative route of administration for drug delivery to the

brain[13, 14]. Intranasal administration allows transport of drugs to the brain circumventing

BBB, thus providing better option to target drugs to the brain[15-19]. Microemulsion lower

the skin irritation: alcohol-free microemulsions have been reported with much lower

irritation potential.

CHALLENGES IN NOSE TO BRAIN DRUG DELIVERY VIA

MICROEMULSION

1. The main problem in a microemulsion application is a high concentration and a

narrow range of physiologically acceptable surfactants and co-surfactants[48, 49].

2. Large surfactant concentration (10-40%) determines their stability[50].



3. Selection of components: if the systems are to be used topically, selection of

components involves a consideration of their toxicity, irritation and sensitivity[51].

4. Nasal congestion due to cold or allergies may interfere with absorption of drug

through nasal mucosa.

5. Delivery is expected to decrease with increasing molecular weight of drug.

6. Some therapeutic agents may be susceptible to partial degradation in the nasal

mucosa or may cause irritation to the mucosa.

7. Concentration achievable in different regions of the brain and spinal cord varies

with each agent.

8. Fluidity of interfacial film should be low to promote the formulation of

microemulsion[52].

FORMULATION OF MICROEMULSIONS

Microemulsions are isotropic systems, which are difficult to formulate, than

ordinary emulsions because formulation is a highly specific process involving

spontaneous interactions among the constituent molecules. Generally, the microemulsion

formulation requires following components:

a) Oil Phase: Toluene, Cyclohexane, mineral oil or vegetable oils, silicone oils or esters

of fatty acids etc. have been widely investigated as oil components[53].

b) Aqueous phase: Aqueous phase may contain hydrophilic active ingredients and

preservatives. Some workers have utilized buffer solutions as aqueous phase.

c) Primary surfactant: The surfactants are generally ionic, non ionic or amphoteric. The

surfactants chosen are generally for the non ionic group because of their good cutaneous

tolerance. Only for specific cases, amphoteric surfactants are being investigated[48, 49].

d) Secondary surfactant (cosurfactant): In most cases, single-chain surfactants alone are

unable to reduce the o/w interfacial tension sufficiently to enable a microemulsion to

form[45,54]. The presence of co-surfactants allows the interfacial film sufficient flexibility

to take up different curvatures required to form microemulsion over a wide range of

composition [53-57]. Co surfactants originally used were short chain fatty alcohols

(pentanol, hexanol, benzyl alcohol). These are most often polyols, esters of polyols,

derivatives of glycerol and organic acids. Their main purpose is to make inter facial film

fluid by wedging themselves between the surfactant molecules.



PREPARATION OF MICROEMULSION

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 different components are mixed. Microemulsions are formed along with

various association structures (including emulsion, 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 equilibria 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,

pseudo ternaryphase 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 Fig.(3).

Figure 3 Pseudoternary phase diagram of oil, water and surfactant showing microemulsion region.

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 the metastable systems are not included. The methodology has been

comprehensively discussed by Shafiq-un-Nabi et al[58].



2. Phase Inversion Method:

Phase inversion of microemulsions 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 temperatures to a w/o

microemulsion at higher temperatures (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 parameters

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 surfactants

form flexible monolayer at the o/w interface resulting in a bicontinuous microemulsion at

the inversion point.

CHARACTERIZATION OF MICROEMULSION

The characterization of these systems is highly challenging due to their small

droplet size with fluctuating boundaries and complex structure. The droplet size,

viscosity, density, turbidity, refractive index, phase separation and pH measurements

shall be performed to characterize the microemulsion. The droplet size distribution of

microemulsion vesicles can be determined by either light scattering technique or electron

microscopy. This technique has been advocated as the best method for predicting

microemulsion stability.

1. Dynamic light-scattering measurements [3, 59-61]: The DLS measurements are taken at

90° in a dynamic light-scattering spectrophotometer which uses a neon laser of



wavelength 632 nm. The data processing is done in the built-in computer with the

instrument.

2. Polydispersity: This property is characterized by Abbe refractometer.

3. Phase analysis: To determine the type if microemulsion that has formed the phase

system (o/w or w/o) of the microemulsion is determined by measuring the electrical

conductivity using a conductometer.

4. Viscosity measurement: The viscosity of microemulsions of several compositions

can be measured at different shear rates at different temperatures using Brookfield type

rotary viscometer. The sample room of the instrument must be maintained at 37 ± 0.2°C

by a thermobath, and the samples for the measurement are to be immersed in it before

testing.

5. In Vitro Drug Permeation Studies: Determination of permeability coefficient and

flux:

Excised human cadaver skin from the abdomen can be obtained from dead who

have undergone postmortem not more than 5 days ago in the hospital. The skin is stored

at 4oC and the epidermis separated. The skin is first immersed in purified water at 60oC

for 2 min and the epidermis then peeled off. Dried skin samples can be kept at -20oC for

later use. Alternatively the full thickness dorsal skin of male hairless mice may be used.

The skin shall be excised, washed with normal saline and used. The passive permeability

of lipophilic drug through the skin is investigated using Franz diffusion cells with

known effective diffusional area. The hydrated skin samples are used. The receiver

compartment may contain a complexing agent like cyclodextrin in the receiver phase,

which shall increase the solubility and allows the maintenance of sink conditions in the

experiments. Samples are withdrawn at regular interval and analyzed for amount of drug

released.

6. In Vivo Studies:

A. Bioavailability studies: Skin bioavailability of topical applied microemulsion on

rats: Male Sprague–Dawley rats (400–500 g), need to be anesthetized (15 mg/kg

pentobarbital sodium i.p.) and placed on their back. The hair on abdominal skin shall be

trimmed off and then bathed gently with distilled water. Anesthesia should be

maintained with 0.1-ml pentobarbital (15 mg/ml) along the experiment.



Microemulsions must be applied on the skin surface (1.8 cm2) and glued to the skin by

a silicon rubber. After 10, 30 and 60 min of in vivo study, the rats shall be killed by

aspiration of ethyl ether. The drug exposed skin areas shall be swabbed three to four

times with three layers of gauze pads, then bathed for 30 s with running water, wiped

carefully, tape-stripped (X10 strips) and harvested from the animals.

B. Determination of residual drug remaining in the skin on tropical

administration: The skin in the above permeation studies can be used to determine the

amount of drug in the skin. The skin cleaned with gauze soaked in 0.05% solution of

sodium lauryl sulfate and shall bath with distilled water. The permeation area shall be

cut and weighed and drug content can be determined in the clear solution obtained after

extracting with a suitable solvent and centrifuging.

C. Pharmacological Studies: Therapeutic effectiveness can be evaluated for the

specific pharmacological action that the drug purports to show as per stated guidelines.

D. Estimation of Skin Irritancy: As the formulation is intended for dermal application

skin irritancy should be tested. The dorsal area of the trunk is shaved with clippers 24

hours before the experiment. The skin shall be scarred with a lancet. 0.5 ml of product is

applied and then covered with gauze and a polyethylene film and fixed with

hypoallergenic adhesive bandage. The test be removed after 24 hours and the exposed

skin is graded for formation of edema and erythema. Scoring is repeated 72 hours later.

Based on the scoring the formulation shall be graded as ‘non-irritant’, ‘irritant’ and

‘highly irritant’.

7. Stability Studies:

The physical stability of the microemulsion must be determined under different storage

conditions (4, 25 and 40 °C) during 12 months. Fresh preparations as well as those that

have been kept under various stress conditions for extended period of time are subjected

to droplet size distribution analysis. Effect of surfactant and their concentration on size of

droplet is also studied.

APPLICATION OF MICROEMULSION IN BRAIN TARGETING

The treatment of CNS disorders are challenging because of a variety of

formidable obstacles for effective and persistent delivery of drugs. Even though the drugs

used for the treatment of CNS disorders are potent, their clinical failure is often not due



to lack of drug efficacy but mainly due to short comings in the drug delivery approach.

Hence, scientists are exploring the novel approaches so that delivery of the drugs can be

enhanced and /or restricted to the brain and CNS. Many advanced and effective

approaches to the CNS delivery of drugs have emerged in recent years. Intranasal

administration confers a simple, economic, convenient and noninvasive route for rapid

drug delivery to the brain [62-64]. It allows a direct transport of drugs to the brain through

brain barriers [16-19].

1. Treatment of Epilepsy and schizophrenia:

Vyas et al. prepared mucoadhesive microemulsion for an antiepileptic drug

clonazepam 15. The aim was to provide rapid delivery to the rat brain. Brain/blood ratio at

all sampling points up to 8h following intranasal administration of clonazepam

mucoadhesive microemulsion compared to i.v. was found to be 2-fold higher indicating

larger extent of distribution of the drug in the brain. Kwatikar et al [65] prepared

microemulsion containing valproic acid showed a fractional diffusion efficiency and

better brain bioavailability efficiency. Hence microemulsions are the promising approach

for delivery of valproic acid to the brain for treatement of epilepsy.

Florence et al [20] has prepared Clobazam microemulsion and mucoadhesive

microemulsion. Formulations were assessed for the average onset of seizures in

pentylene tetrazole treated mice. This study demonstrated high brain targeting efficiency

of prepared Clobazam mucoadhesive microemulsion and delayed onset of seizures

induced by pentylene tetrazole in mice after intranasal administration of developed

formulation. However, clinical evaluation of the developed formulation may result into a

product suitable for the treatment of acute seizures due to status epileptics and patients

suffering from drug tolerance and hepatic impairment on chronic use in the treatment of

epileptics, schizophrenia and anxiety.

Shende et al[66] prepred microemulsion of lomotrigone from nose to brain

delivery. Intranasal administration allows transport of the drug to the brain circumventing

BBB, thus ptoviding the better option to target drug to the brain with quick onset of

action in case of emergency in epilepsy.

Lorazepam (LZM) is a poorly water-soluble drug which can be used as tranquillizers,

muscle relaxant, sleep inducer, sedative and antiepileptic agent21. However, cosolvent



based parenteral formulations suffer from several disadvantages such as pain and tissue

damage at the site of injection and precipitation of the drug on dilution in several cases

[22]. Furthermore, parenteral administration of the organic cosolvents can also cause

hemolysis[23]. Amit et al[24] has prepared Lorazepam microemulsions and investigate that

microemulsion have very low hemolytic potential and exhibit good physical and

chemical stability and can be considered as a viable alternative to the currently marketed

Lorazepam formulations.

2. Treatment of Migraine:

Migraine treatment has evolved into the scientific arena, but opinions differ on

whether migraine is primarily a vascular or a neurological dysfunction [25, 26]. Sumatriptan

is rapidly but incompletely absorbed following oral administration and undergoes first-

pass metabolism, resulting in a low absolute bioavailability of 14% in humans. [27].

Moreover, the transport of Sumatriptan across the blood-brain barrier (BBB) is very

poor13. Studies have demonstrated that intranasal administration offers a practical,

noninvasive, alternative route of administration for drug delivery to the brain [13, 14].

Vyas et al [18] Prepared mucoadhesive microemulsion of Sumatriptan which shows rapid

and larger extent of selective Sumatriptan nose-to-brain transport compared with

Suspension and Microparticles of the same in rats. Enhanced rate and extent of transport

of Sumatriptan following intranasal administration of microemulsion may help in

decreasing the dose and frequency of dosing and possibly maximize the therapeutic

index.

Shelke et al [67] has reported that Zolmitriptan microemulsion from nose to brain

delivery provide the dual advantages of enhanced bioavailability with rapid onset of

action in treatment of migraine. Tushar et al [68] has investigated zolmitriptan

microemulsions (ZTME) for rapid drug delivery to the brain to treat acute attacks of

migraine and to characterize microemulsions and evaluate biodistribution in rats. Studies

of this investigation conclusively demonstrated rapid and larger extent of transport into

the rat brain following intranasal administration of ZMME and can play a promising role

in the treatment of acute attacks of migraine.

3. As an Antidepressant:



Tiwari et al [28] has developed Eucalyptus oil microemulsion for intranasal

delivery to the brain. This work demonstrated that the microemulsion of eucalyptus oil is

cost effective and efficient formulation which provides the rapid onset in soothing

stimulant and antidepressant action

4. Treatment of angina Pectoris and neurological deficit:

Qizhi Zhang [29] has prepared the microemulsion to improve the solubility and

enhance the brain uptake of nimodipine (NM), which was suitable for intranasal delivery.

The uptake of NM in the olfactory bulb from the nasal route was three folds, compared

with intravenous (i.v.) injection. The ratios of AUC in brain tissues and cerebrospinal

fluid to that in plasma obtained after nasal administration were significantly higher than

those after i.v. administration. These results suggest that the microemulsion system is a

promising approach for intranasal delivery of NM for the treatment and prevention of

neurodegenerative diseases.

Jing Yao [69] has prepared hyaluronic acid chitosan-based microemulsion (HAC-

ME) containing nobiletin and determines its distribution in mice brain following i.v.

administration. Based on AUC0–t, MRT and Cmax, HAC-ME delivered more nobiletin to

the brain compared to nobiletin solution. These results indicate that HAC-ME may be

presented as potential candidates for delivering more drugs into the brain

5. Treatment of Amnesia:

Jogani and Misra, 2008 has studied microemulsion /mucoadhesive microemulsion

of tacrine, assessed its pharmacokinetic and pharmacodynamic performances for brain

targeting and for improvement in memory in scopolamine-induced amnesic mice [70]. The

results demonstrated rapid and larger extent of transport of tacrine into the mice brain and

faster regain of memory loss in scopolamine-induced amnesic mice after intranasal

microemulsion administration.

OTHER APPLICATION OF PHARMACEUTICAL MICROEMULSION

1. Tumor Targeting:

Microemulsions successfully utilize to deliver the various antineoplastics/

antitumor agents, viz. doxorubicin, idarubicin, tetrabenzamidine derivative[71].

Cyclosporine delivery has remained a challenge for the formulation scientists. It is an

immunosuppressive agent and is widely used in recipients of organ transplants and in



various autoimmune diseases. The inherent insolubility of the cyclosporine provides the

major role for the low and variable bioavailability and low formulation stability during

storage. Due to poor bioavailability, higher doses may be needed which may result in

undesirable adverse side effects such as nephrotoxicity and renal side effects. Sandoz Ltd.

introduced an improved formulation later under the trademark Neoral® according to the

composition disclosed in US Patent 5342625. The Neoral formulation was a

microemulsion pre-concentrate which contained cyclosporine in an anhydrous oily

vehicle, medium chain triglycerides, surfactants, glycerol and alcohol which exhibited

better and more consistent bioavailability [72].

Maranh et al [73] suggested the utility of microemulsions as vehicles for the

delivery of chemotherapeutic or diagnostic agents to neoplastic cells while avoiding

normal cells. They claimed a method for treating neoplasms, wherein neoplasms cells

have an increased number of LDL (low density, lipoprotein) receptors compared to

normal cells. The microemulsion comprised of a nucleus of cholesterol esters and not

more than 20% triglycerides surrounded by a core of phospholipids and free cholesterol

and contained a chemotherapeutic drug. Microemulsions were similar in chemical

composition to the lipid portion of low density lipoprotein (LDL), but did not contain the

protein portion.

These artificial microemulsion particles incorporated plasma apolipoprotein E

(apo E) on to their surface when they were injected in the blood stream or incubated with

plasma. The apolipoprotein E served as a linking element between the particles of the

microemulsion and the LDL receptors. The microemulsions could then be incorporated

into cells via receptors for LDL and delivered the incorporated molecules.

Thus, higher concentration of anticancer drugs could be achieved in the neoplastic

cells that have an increased expression of the receptors. In this way toxic effects of these

drugs on the normal tissues and organs could be avoided. In human subjects, they

observed no change in the plasma kinetics of the radioactively labeled microemulsion

containing carmustine or cytosine-arabinoside thereby confirming that the incorporation

of these drugs did not diminish the capacity of the microemulsion to incorporate apo E in

the plasma and bind to the receptors. Shiokawa and coworkers reported a novel

microemulsion formulation for tumor targeted drug carrier of lipophilic antitumor



antibiotic aclacinomycin A (ACM) [74]. Their findings suggested that a folate-linked

microemulsion is feasible for tumor targeted ACM delivery. The study showed that folate

modification with a sufficiently long PEG chain on emulsions is an effective way of

targeting emulsion to tumor cells.

Intravenous administration of cisplatin produces adverse effects like ototoxicity,

renal failure, nephrotoxicity and chronic neurotxicity[75]. Hence, to overcome these

inherent drawbacks associated with parenteral drug delivery of cisplatin an attempt is

being made by Doizad et al[76] to provide cisplatin in the form of Solid-Lipid

Nanoparticles using microemulsion technology to reduce the adverse effects and to

enhance therapeutic efficacy of the drug.

Dongxing et al [77] has investigated the levels of raltitrexed (RTX) in blood and

different brain tissues in rats and to find out whether there is any direct drug transport

from nasal cavity to brain tissues following intranasal (i.n.) administration. AUC values

in four brain regions by the nasal route were 54 to 121 fold compared with the i.v. route.

Results showed that antineoplastic RTX could be directly transported into the brain tissue

via the olfactory pathway in rats.

2. As a permeation enhancer:

Microemulsions may affect the permeability of drug in the skin. In this case, the

components of microemulsions serve as permeation enhancers. Several compounds used

in microemulsions have been reported to improve the transdermal permeation by altering

the structure of the stratum corneum. For example, short chain alkanols are widely used

as permeation enhancers 3. The dispersed phase, lipophilic or hydrophilic (o/w or w/o

type) can act as a potential reservoir of lipophilic or hydrophilic drugs that can be

partitioned between the dispersed and the continuous phases. Coming in contact with a

semi permeable membrane, such as skin or mucous membrane, the drug can be

transported through the barrier71. Microemulsions improve the transdermal delivery of

several drugs over the conventional topical preparations such as emulsions [78].

3. Parenteral Delivery:

Drugs with poor solubility are difficult to administer through parenteral route

because of the extremely low amount of drug actually delivered to a targeted site.

Microemulsion formulations are advantageous in Parenteral drug delivery because of the



fine particle microemulsion is cleared more slowly and, therefore, have a longer

residence time in the body. An alternative approach was taken by Von Corsewant and

Thoren[48] in which C3-C4 alcohols were replaced with parenterally acceptable co-

surfactants, polyethylene glycol (400) / polyethylene glycol (660) 12-hydroxystearate /

ethanol, while maintaining a flexible surfactant film and spontaneous curvature near zero

to obtain and almost balanced middle phase microemulsion.

4. Oral Drug Delivery:

Microemulsions formulations offer the several benefits over conventional oral

formulation including increased absorption, improved clinical potency, and decreased

drug toxicity[79]. Literature survey revealed that microemulsion is ideal candidate for oral

delivery of drugs such as steroids, hormones, diuretic and antibiotics. Because of low oral

bioavailability, most protein drugs are only available as parenteral formulations.

However, peptide drugs have an extremely short biological half life when administered

parenterally, so require multiple dosing. A microemulsion formulation of cyclosporine,

named Neoral® has been introduced to replace Sandimmune®, a crude oil-in-water

emulsion of cyclosporine formulation. Neoral® is formulated with a finer dispersion,

giving it a more rapid and predictable absorption and less inter and intra patient

variability [80].

5. Ocular Drug Delivery: O/W microemulsions have been investigated for ocular

administration, to dissolve poorly soluble drugs, to increase absorption and to attain

prolong release profile. The microemulsions containing pilocarpine were formulated

using lecithin, propylene glycol and PEG 200 as co-surfactant and IPM as the oil phase.

The formulations were of low viscosity with a refractive index lending to ophthalmologic

applications [44].

6. Application in Biotechnology:

Many enzymes including lipases, esterases, dehydrogenases and oxidases often

function in the cells in microenvironments that are hydrophobic in nature. In biological

systems many enzymes operate at the interface between hydrophobic and hydrophilic

domains and these usually interfaces are stabilized by polar lipids and other natural

amphiphiles. Enzymatic catalysis in microemulsions has been used for a variety of



reactions, such as synthesis of esters, peptides and sugar acetals transesterification;

various hydrolysis reactions and steroid transformation.

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For Correspondence: Ram Chand Dhakar Dept. of Pharmacy, IEC College of Eng & Technology, KP-I, Gr Noida, INDIA -201308 E-mail: [email protected] Mob. +919310440484

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MICROEMULSION AS A CARRIER FOR NOSE TO BRAIN TARGETING… · MICROEMULSION AS A CARRIER FOR NOSE TO BRAIN TARGETING: ... 1Dept. of Pharmacy, ... because of its improved drug solubilization