Microemulsion: A Potential Novel Drug Delivery System
Naresh Mandavi1, Nazneen Ansari1, Ravi Bharti1, N Syed Abdul Kader1, Gyanesh Kumar Sahu2, Harish Sharma1*
1Shri Shankaracharya Technical Campus, Shri Shankaracharya Group of Institutions, Faculty of Pharmaceutical Sciences, Bhilai, CG, India. (490020)
2Rungta College of Pharmaceutical Sciences and Research, Bhilai, (C.G.)
*Corresponding Author E-mail: harishsharma.817@rediffmail.com
ABSTRACT:
Microemulsions are isotropic, thermodynamically stable transparent (or translucent) systems of oil, water and surfactant, frequently in combination with a cosurfactant with a droplet size usually in the range of 20-200 nm. They have emerged as novel vehicles for drug delivery which allow controlled or sustained release for ocular, percutaneous, topical, transdermal, and parenteral administration of medicaments. Microemulsions can be easily distinguished from normal emulsions by their low viscosity, transparency and more accurately their thermodynamic stability. Microemulsions have a very crucial importance in the drug delivery system as well as in the industrial process. They can be used to optimize drug targeting without a concomitant increase in systemic absorption. The role of microemulsion in providing novel solutions to overcome the problems of poor aqueous solubility of highly lipophilic drug compounds and provide high, more consistent and reproducible bioavailability. The objective of this review is to provide an overview of the structures, methods of microemulsion formation, techniques which may be used for characterization and application.
KEYWORDS: Microemulsion, Surfactant, Co-surfactant.
INTRODUCTION:
Novel drug delivery systems are designed to achieve a continuous delivery of drugs at predictable and reproducible kinetics over an extended period of time in the circulation. The potential advantages of this concept include minimization of drug related side effects due to controlled therapeutic blood levels instead of oscillating blood levels, improved patient compliance due to reduced frequency of dosing and the reduction of the total dose of drug administered. The method by which a drug is delivered can have a significant effect on its efficacy.
Some drugs have an optimum concentration range within which maximum benefit is derived, and concentrations above or below this range can be toxic or produce no therapeutic benefit at all. On the other hand, the very slow progress in the efficacy of the treatment of severe diseases, has suggested a growing need for a multidisciplinary.(1)
Carriers Used In Novel Drug Delivery System:
The novel drug delivery systems also have the advantage of penetrating more efficiently into the circulation than do non particulate systems, such as conventional formulations, so long as the size is selected in an appropriate manner. This provides a high local concentration over a prolonged period(2). The drug-loaded vesicular and particulate delivery systems (liposomes, polymeric microspheres, and solid lipid nanoparticles) for topical treatment are advantageous compared to conventional available topical delivery system. The novel carrier systems that are under investigation for application and treatment of acne include liposome, niosome, microsponge, microemulsion, microsphere, SLN, hydrogel, aerosol, fullerenes and so forth. It is given in figure-1,(3;4)
Fig 1: Different Carrier Systems of NDDS
Microemulsion:
The term "microemulsion" refers to a thermodynamically stable, isotropically clear dispersion of two immiscible liquids, such as oil and water, which is stabilized by an interfacial film of surfactant molecules. Surfactant molecules contain both a polar as well as an a polar group. So they exhibit a very peculiar behavior, firstly, they get adsorbed at the interface, where they can fulfill their dual affinity with hydrophilic groups located in aqueous phase and hydrophobic groups in oil or air. Secondly, they reduce mismatching with solvent by Micellization Process (5). Microemulsions are currently the subject of many investigations because of their wide range of potential and actual utilizations. The high capacity of microemulsions for drugs makes them attractive formulations for pharmaceuticals. These systems also offer several benefits for oral administration, including increased absorption, improved clinical potency and decreased toxicity.(6)
Advantages of Microemulsion(7,8,9):
1. Microemulsions are thermodynamically stable system and allows self-emulsification of the system.
2. Microemulsions act as supersolvents for drug, can solubilise both hydrophilic and lipophilic drugs including drugs that are relatively insoluble in both aqueous and hydrophobic solvents.
3. Microemulsions have low viscosity compared to primary and multiple emulsions.
4. The use of microemulsion as delivery systems can improve the efficacy of a drug, allowing the total dose to be reduced and thus minimizing side effects.
5. The use of microemulsion as delivery systems can improve the efficacy of a drug, allowing the total dose to be reduced and thus minimizing side effects
6. Having the ability to carry both lipophilic and hydrophilic drugs.
7. The dispersed phase, lipophilic or hydrophilic (O/W, or W/O microemulsions) can act as a potential reservoir of lipophilic or hydrophilic drugs, respectively.
Limitation of Microemulsion(7,8,9)
1. Having limited solubilizing capacity for high melting substances.
2. Require large amount of Surfactants for stabilizing droplets. Microemulsion stability is influenced by environmental parameters such as temperature and pH.
Structure of Microemulsion:
Microemulsions or Micellar emulsion are dynamic system in which the interface is continuously and spontaneously fluctuating(10). Structurally, they are divided in to oil in water (o/w), water in oil (w/o) and bi-continuous microemulsions. In w/o microemulsions, water droplets are dispersed in the continuous oil phase while o/w microemulsions are formed when oil droplets are dispersed in the continuous aqueous phase. In system where the amounts of water and oil are similar, the bi-continuous microemulsions may result(11). The mixture oil water and surfactants are able to form a wide variety of structure and phase depending upon the proportions of component.
Fig 2: Microemulsion Structure
Classification of Microemulsion:
Composition classification of microemulsions(12):
1. Oil in water microemulsions wherein oil droplets are dispersed in the continuous aqueous phase.
2. Water in oil microemulsions wherein water droplets are dispersed in the continuous oil phase.
3. Bi-continuous microemulsions where in microdomains of oil and water are interdispersed within the system.
Winsor classification of Microemulsion(13,14,15)
Winsor I:
With two phases, the lower (o/w) microemulsion phases in equilibrium with the upper excess oil.
Winsor II: With two phases, the upper microemulsion phase (w/o) microemulsion phases in equilibrium with lower excess water.
Winsor III: With three phases, middle microemulsion phase (o/w plus w/o, called bi-continuous) in equilibrium with upper excess oil and lower excess water.
Winsor IV: In single phase, with oil, water and surfactant homogenously mixed.
Table 1: Comparison between emulsion and microemulsion(16, 39)
|
Sr. No. |
Specification |
Nanoemulsion |
Microemulsion |
|
1
|
Appearance |
Nanoemulsions are part of a broad class of multiphase colloidal dispersions. It is dispersions of nanoscale droplets formed by shear-induced rupturing. |
Microemulsions are transparent or translucent as their droplet diameter are less than ¼ of the wave length of light, they scatter little light. |
|
2 |
Optical Isotropy |
Isptropic |
Isotropic |
|
3 |
Formation |
Mechanical shear |
Self assembly |
|
4 |
Stability |
Kinetically stable/ metastable, thermodynamically unstable |
Thermodynamically Stable Long shelf life |
|
5 |
Microstructure |
Dynamic |
Dynamic |
|
6 |
Droplet Size |
1-100nm |
20-200nm |
|
7 |
Droplet Shape |
Nanaoemulsion consist of spherical in shape due to that, small-sized droplet with its high surface area allowing effective transport of the active to the bioactive effects |
They constantly evolve between various structures ranging from droplet like swollen micelles to bicontinuous structure |
|
9 |
Molecular Packing |
Efficient |
Efficient |
|
10 |
Stability |
Thermodynamically stable , long shelf-life |
Thermodynamically stable, long shelf-life |
|
11 |
Phase |
Monophase |
Monophase |
|
12 |
Viscosity |
Low |
Low |
|
13 |
Interfacial tension |
Low |
Ultra low |
|
14. |
Theories |
Surface tension theory Interfacial theory
|
Thermodynamic theory Solubilisation theory Interfacial theory |
Components of Microemulsion System(17):
Various ingredients are used in the formulation and development of microemulsions. Mainly oil and surfactants are used in microemulsion they should be biocompatible, non-toxic and clinically acceptable. Main components of microemulsion are
1. Oil phase
2. Aqueous phase
3. Surfactant
4. Co-surfactants
5. Co-solvents
Oil phase(18):
Oil is one of the most important components of microemulsion because it can solubilise the required dose of the lipophilic drug and it increases the fraction of lipophilic drug transported via the intestinal lymphatic system. Oil is defined as any liquid having low polarity and low miscibility with water. The examples of such phase are cyclohexane, mineral oil, toulene, and vegetable oil etc.
Aqueous phase(19) :
The aqueous phase may contain hydrophilic active ingredients and preservatives. Buffer solutions are used as aqueous phase by some researchers
Surfactant(20,21) :
Surfactants are the molecules which when present in low concentration will adsorb to the surface of interfaces of a system and alter the interfacial energies of the system. The interfacial energy is the work required to create unit area of an interface. The actual purpose of surfactant is to lower the interfacial tension to negligible value that facilitates the process of dispersion during preparation of microemulsion. It presents the microemulsion with pertinent lipophilic character to furnish accurate curvature. This adsorption behavior can be attributed to solvent nature and to the chemical nature of surfactant that combines both polar and non-polar group in a single molecule. Due to their dual nature these amphiphiles “sit” at interfaces so that their hydrophobic moiety is repelled from strong solvent interactions.
Co-surfactants(22) :
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 interfacial layer, increasing the fluidity of interfacial film by penetrating into surfactant layer. Short to medium chain length alcohols are generally added as cosurfactants helping in to increase the fluidity of interface.
Co-solvents(23,24) :
The production of stable microemulsion requires relatively high concentrations (generally more than 30% w/w) of surfactants. Organic solvents such as, ethanol, propylene glycol (PG), and polyethylene glycol (PEG) are suitable for oral delivery, and they enable the dissolution of large quantities of either the hydrophilic surfactant or the drug in the lipid base. These solvents can even act as co-surfactants in microemulsion systems.
Method of Preparation:
1. Phase titration method:
Microemulsions are prepared by spontaneous emulsification Method(25)which is illustrated with help of phase diagrams. Phase diagram construction is practical approach to study complex series of interaction which occurs when different components are mixed. The aspect of the phase diagram is phase equilibrium and demarcation of phase boundaries. Most often pseudo-ternary phase diagrams are constructed to figure out microemulsion zone as quaternary phase diagram is time consuming and difficult to interpret(26).
2. Phase inversion method:
Phase inversion of microemulsion happens upon addition of excess of dispersed phase. Phase inversion leads to radical physical changes as change in particle size that alters drug release(27). During cooling, this system crosses the point of zero spontaneous curvature and minimal surface tension, prompting the formation of finely dispersed oil droplets(28). Microemulsions can be prepared by controlled addition of lower alkanols (butanol, pentanol and hexanol) to milky emulsions to produce transparent solutions comprising dispersions of either o/w or w/o or colloidal dispersions. The lower alkanols are called co-surfactants. They lower the interfacial tension between oil and water sufficiently low for almost spontaneous formation(29).\
Factor Affecting Formulation of Microemulsion System:
1. Property of surfactant(30) :
Surfactant contains two group lipophilic and hydrophilic groups. Hydrophilic single chain surfactants such as cetylethyl ammonium bromide dissociate completely in dilute solution and have a tendency to form o/w microemulsion. When the surfactant is in presence of salt or when high concentration of surfactant is used, degree of dissociation of polar groups becomes lesser and resulting system may be w/o type.
2. Property of Oil Phase(31) :
Oil phase also influence curvature by its ability to penetrate and Swell the tail group region of the surfactant monolayer, swelling of tail results into an increased negative curvature to w/o microemulsion.
3. Packing Ratio (32) :
HLB of surfactant determines the type of microemulsion through its influence on packing and film curvature. The analysis of film curvature for surfactant association`s leading to the formation of microemulsion.
4. Temperature(33) :
Temperature is extremely important in determining the effective head group size of nonionic surfactants. At low temperature, they are hydrophilic and form normal o/w system. At higher temperature, they are lipophilic and form w/o systems. At an intermediate temperature, microemulsion coexists with excess water and oil phases and forms bicontinuous structure.
Applications Of Microemulsion:
Fig 3: Applications of Microemulsions
Parenteral Delivery(34) :
Parenteral administration (especially via the intravenous route) of drugs with limited solubility is a major problem in industry because of the extremely low amount of drug actually delivered to a targeted site. Microemulsion formulations have distinct advantages over macroemulsion systems when delivered parenterally because of the fine particle microemulsion is cleared more slowly than the coarse particle emulsion and, therefore, have a longer residence time in the body.
Oral Delivery(35) :
Microemulsion formulations offer the several benefits over conventional oral formulation including increased absorption, improved clinical potency, and decreased drug toxicity. Therefore, microemulsions have been reported to be ideal delivery of drugs such as steroids, hormones, diuretic and antibiotics.
Topical Delivery(36) :
Topical administration of drugs can have advantages over other methods for several reasons, one of which is the avoidance of hepatic first pass metabolism of the drug and related toxicity effects. Second is the direct delivery and targetability of the drug to affected area of the skin or eyes.
Ocular and Pulmonary Delivery(37) :
For the treatment of eye diseases, drugs are essentially delivered topically. 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.
Microemulsions in biotechnology(38) :
Many biocatalytic and enzymatic reactions are conducted in aquo-organic or pure organic as well as in biphasic media. Their use is seriously limited because they can inactivate or denature the biocatalysts. Recently, interest on microemulsions is being focused for various applications in biotechnology, viz, enzymatic reactions, immobilization of proteins and bioseparation.
CONCLUSION:
Now a days microemulsions have been shown to be able to protect labile drug, control drug release, increase bioavailability, increase drug solubility, reduce patient variability increase the rate of absorption, helps solubilize lipophilic drug, various routes like tropical, oral and intravenous can be used to deliver the product, helpful in taste masking, provides and increases patient compliance. Microemulsion drug delivery system is most attractive and suitable area of research, offering not only many challenges to overcome but also potential extra ordinary benefits. Moreover, it has proven possible to formulate preparations suitable for most routes of administration.
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Received on 25.04.2018 Modified on 11.06.2018
Accepted on 11.07.2018 ©A&V Publications All right reserved
Res. J. Pharm. Dosage Form. & Tech. 2018; 10(4): 266-271.
DOI: 10.5958/0975-4377.2018.00039.3