INTRODUCTION:

Micelle: ^1-5

Micelle is a “particle of colloidal dimensions that exists in equilibrium with the molecules or ions in solution from which it is formed.” A micelle is an aggregate of surfactant molecules dispersed in a liquid colloid. A typical micelle in aqueous solution forms an aggregate with the hydrophilic "head" regions in contact with surrounding solvent, sequestering the hydrophobic single tail regions in the micelle centre. This phase is caused by the insufficient packing issues of single tailed lipids in a bilayer. The difficulty filling all the volume of the interior of a bilayer, while accommodating the area per head group forced on the molecule by the hydration of the lipid head group leads to the formation of the micelle. This type of micelle is known as a normal phase micelle (oil-in-water micelle). Inverse micelles have the head groups at the centre with the tails extending out (water-in-oil micelle). Micelles are approximately spherical in shape. Other phases, including shapes such as ellipsoids, cylinders, and bilayer are also possible.

The shape and size of a micelle is a function of the molecular geometry of its surfactant molecules and solution conditions such as surfactant concentration, temperature, pH and ionic strength. The process of forming micelle is known as Micellization and forms part of the phase behavior of many lipids according to their polymorphism.

Fig. 1: Cross section of micelle; liposome

Micelles are well oriented surfactant molecules having hydrophilic head and hydrophobic tail. Micelle may contain 50 or more monomeric units of surface active agent. There is equilibrium between monomers and micelle. Micelles have half life of centisecond or even less. Micellization minimizes the contact between hydrophobic portion and surrounding water.

Forces involved in micelle formation: ^{6- 8}

Forces based on hydrophobicity:

1. Head-head attraction.-:

There are always attractive forces between the head group of one micelle and head group of another micelle in the system.

2. Tail-tail attraction-:

Tail portion of all the monomers in single micelle exhibit attractive forces so as to construct inner hydrophobic core.

3. Tail-head repulsion-:

This is nothing but a force exhibited due to opposite charges present on the head and tail portion of the micelle or monomer.

4. Head-tail repulsion-:

This is again nothing but a force exhibited due to opposite charges present on the head and tail portion of the micelle or monomer.

Micellar structure:

In case of ionic micelles, there are three main parts-

1. Micellar liquid core: ^6-11

Liquid core is formed by hydrocarbon chain with the head group projecting out in water. Techniques which are used to detect nature of micellar core are as follows:

i. Fluorescent probes: It shows fluorescence in non polar region only and they are non fluorescent in water.

Eg. 8-anilino-1-napthalene-sulphonate

With respect to fluorescence phenomenon, there are two techniques of micellar core determination-

A. Fluorescent depolarization B. Excitement fluorescence

Drawbacks- i. Uncertainty of location of probe.

Possible perturbation of micro environment.

ii. Hydrocarbon probes: used are pyrene and methyl anthracene. It was concluded that interior of the micelle of several long chain cationic surfactants were of liquid in nature.

iii. ESR spectra: is used to measure electron spin resonance from free radicals which are incorporated in probes within micelle. Restricted motion of probe results in hyperfine splitting in ESR spectrum and broadening of the spectral lines indicates high local viscosity.

iv. Raman spectra and NMR spectra: is used to detect conformational state of hydrocarbon chain in micellar core. Raman spectra indicated that in crystalline state, hydrocarbon chain exists in all-trans conformation while in micellar state it is in gauche conformation.

2. Stern layer: ^{12, 13}

The layer which immediately next to the core is called as stern layer which contains ionic head groups and (1-alpha) n counter ions. Stern layer contains inner part of the electric double layer surrounding the micelle. The electric potential, at the interface between micellar core and surrounding water is estimated by Gouy-chapman theory. Measurement of electric potential is done by probes of molecular sizes which are known to get solubilized at the core water interface and which does not disturb the system.

Eg. Hydrogen ion concentration at the micellar surface was determined by pH indicators like bromophenol blue and bromocresol green. The apparent pKa of the indicators when solubilized in ionic micelle differed from that in bulk and this shift was related to electric potential assuming a Boltzmann distribution of hydrogen ion concentration at the surface.

Drawback-

Equilibrium of indicators at the micellar surface is affected by dielectric constant which is lower at the surface compared to the bulk solution. Dielectric constant for stern layer is intermediate between 79 for water and it is 2 for hydrocarbons.

3. Gouy-chapman layer: ^{12, 13}

It is the outer layer which more diffused in nature and it contains remaining counter ions which are not present in the stern layer .It may get extended up to the aqueous environment.

Micelle shape: ^{7, 8}

Micelles are dynamic structures with a liquid core. It is not a rigid structure with a precised shape hence an average micelle shape is considered. For experimental interpretation, micellar sphericity is assumed. As no hole is present at the centre of the micelle, the micellar radius is always limited by maximum possible extension of hydrocarbon chain.

The shape of the micelle = VH/lc.ao

Where, VH = volume of the hydrophobic group in the micellar core.

lc= length of the hydrophobic group in the core.

ao= cross sectional area occupied by hydrophilic group at the micelle –solution interface.

Table: 1 Correlation between the parameter VH/ lc.ao and shape of micelle

Micellar shape	VH/ lc.ao
Spherical in aqueous medium	0 to1/3
Cylindrical in aqueous medium	1/3 to ½
Lamillar in aqueous medium	1/2 to 1
Reversed in non-aqueous medium	>1

A spherical shape micelle is possible only when many oxyethylene chains are embeded in the hydrophobic core. Eg. Triton x-100 micelle was considered to be spherical. Oblate shape is favoured when head group repulsion is strong. Non ionic and ionic surfactants in presence of electrolyte favour oblate shape. Eg. n-alkylpolyoxyethylene glycol monoethers, Lubrol WX. For the ionic surfactants, oblate shape get transited to prolate ellipsoid shape with the increase in the solution concentration provided that added salts are absent. Israela chvilli et. al. rejected the oblate shape due to excessive curvature of peripheral region and excessive thickness of the central region. He proposed the distorted oblate spheroidal shape resembling RBC in shape. Micellar shape get affected by factors such as temperature, concentration, presence of added electrolyte etc. increase in one of these parameters results in shape transition of the micelle from near spheroidal shape to asymmetric form. In case of cetyltrimethylammonium bromide (CTAB), flexible rod like aggregates is formed at higher concentration. X-ray scattering measurements of CTAB shown that at concentration 0.15M (approx), CTAB micelles undergoes transition from spherical to rod shape.

Spherical Micelle

Cylindrical micelle

Lamellar Micelle

Fig. 2: Micelles of various shapes

Types of micelles:

1. Monomeric micelle:⁶^-8

Individual surfactant molecules that are in the system but are not part of a micelle are called "monomers." In micelle, the hydrophobic tails of several surfactant molecules assemble into an oil-like core the most stable form of which has no contact with water. By contrast, surfactant monomers are surrounded by water molecules that create a "cage" of molecules connected by hydrogen bonds. This water cage is similar to ice-like crystal structure.

Micelles are dynamic species; there is a constant rapid interchange of surfactant molecules between the micelle and the bulk solution. Micelles cannot, therefore, be regarded as rigid structures with a defined shape, although an average micellar shape may be considered and Micelles are labile entities formed by the non-covalent aggregation of individual surfactant monomers. Therefore, they can be spherical, cylindrical, or planar (disc or bilayer). Micelle shape and size can be controlled by changing the surfactant chemical structure as well as by varying solution conditions such as temperature, overall surfactant concentration, surfactant composition (in the case of mixed surfactant systems), ionic strength and pH. In particular, depending on the surfactant type and on the solution conditions, spherical micelles can grow one-dimensionally into cylindrical micelles or two-dimensionally into bilayer or discoidal micelles. Spherical micelles exist at conc. relatively close to the CMC. At higher concentration lamellar micelles have an increasing tendency to form and exist in equilibrium with spherical micelle.

Micelle growth is controlled primarily by the surfactant heads, since both one dimensional and two dimensional growth require bringing the surfactant heads closer to each other in order to reduce the available area per surfactant molecule at the micelle surface and hence the curvature of the micelle surface.

Solution at CMC Solution above CMC

Fig.3: formation of micelle from monomer

In polar solvent, the hydrophilic "heads" of surfactant molecules are always in contact with the sequestering solvent and the hydrophobic single tail regions in the micelle centre called normal micelle (oil-in-water micelle). This phase is caused by the insufficient packing issues of single tailed lipids in a bilayer. The difficulty filling all the volume of the interior of a bilayer, while accommodating the area per head group forced on the molecule by the hydration of the lipid head group leads to the formation of the micelle.¹⁴ One of the most important applications of Micellization in the context of pharmaceuticals is their ability to solubilize drugs of poor aqueous solubility.

Fig. 4 Schematic illustration of the reversible monomer-micelle thermodynamic equilibrium.

2. Reverse micelle:¹⁵^-17

In a non-polar solvent, the lipophilic "tails" of surfactant molecules have less contact with water or the exposure of the hydrophilic head groups to the surrounding solvent that is energetically unfavorable. Therefore, the head groups are pulls at the centre with the tails extending out called as Inverse/Reverse micelle (water-in-oil micelle). Dipole–dipole interactions hold the hydrophilic heads of the surfactant molecules together in the core, and in certain cases hydrogen bonding between head groups can also occur. Reverse micelle formed by the aggregation of the 3 to 20 monomer by oil soluble surfactant. e.g. Scheme of an inverse micelle formed by phospholipids in an organic solvent.

Fig.5(a):Reverse Micelle (in Non polar solvent)

Fig.5(a): Normal Phase Micelle

In the same way that normal micellar systems can be used for solubilizing hydrophobic substances in an aqueous solution, reversed micellar systems may be used for solubilizing water-soluble drugs in an oil-continuous system.

Advantages of reverse micelle:

· To solubilize water soluble drugs in an oil continuous system.

· The release rate of water soluble drug may be controlled.

· Masking of bitter taste for extensively water soluble drugs.

· Passive drug targeting.

3. Polymeric micelle: ^18-21

In drug delivery, special attention has been given to the polymeric micelles. Polymeric micelles are composed of block or graft copolymers. Polymeric micelles are formed from copolymers consisting of both hydrophilic and hydrophobic monomer units, such as PEO and PPO (polyethylene oxide and polypropylene oxide), respectively. These amphiphilic block co-polymers with the length of the hydrophilic block exceeding the length of the hydrophobic block can form spherical micelles in aqueous solution. The micellar core consists of the hydrophobic blocks and the shell region consists of the hydrophilic blocks. The PEO coating has been shown to prevent subsequent recognition by the macrophages of the reticuloendothelial system (RES), allowing the micelles to circulate longer and deliver drugs more effectively to the desired sites. Block copolymers are generally linear polymers that are composed of a sequence of at least two polymer segments that differ in physico-chemical properties, e.g. charge and/or polarity.

Formations of polymeric micelles from different types of amphiphilic block co-polymers. In graft copolymers, side chain segments are grafted to a main polymer chain. Fully hydrophilic block or graft copolymers in which one of the segments carry a charge may form stable complexes in water together with oppositely charged (macro) molecules, resulting in, for instance, so-called poly ion complex micelles or polyelectrolyte micelles.On the other hand, so-called amphiphilic block copolymers are capable to self-assemble, when placed in a solvent that is selective for one of the polymeric segments, to form micelles, vesicles or gels. In an aqueous environment, such self-assembled structures are interesting for encapsulation and (controlled) release of a variety of drugs.

Drug loading of amphiphilic block copolymer micelles is generally accomplished by -

(a) Dissolving the polymer and the hydrophobic drug in an organic solvent and subsequent dialyzing against water or diluting in water and evaporating the solvent.

(b) Another method that is reported occasionally is the ‘spontaneous’ hydration of a polymer/drug mixed film.

An interesting class of block copolymers is amphiphilic or double hydrophilic block copolymers that respond to an external stimulus, such as temperature, pH, electrolyte, redox potential or even light. These are especially interesting for drug delivery systems, because the micelles can associate or dissociate (encapsulate or release their contents) upon an external trigger. Micelles formed by self-assembly of amphiphilic block copolymers (5-50 nm) in aqueous solutions are of great interest for drug delivery applications. The drugs can be physically entrapped in the core of block copolymer micelles and transported at concentrations that can exceed their intrinsic water- solubility. Moreover, the hydrophilic blocks can form hydrogen bonds with the aqueous surroundings and form a tight shell around the micellar core. As a result, the contents of the hydrophobic core are effectively protected against hydrolysis and enzymatic degradation. In addition, the corona may prevent recognition by the reticuloendothelial system and therefore preliminary elimination of the micelles from the bloodstream. A final feature that makes amphiphilic block copolymers attractive for drug delivery applications is the fact that their chemical composition, total molecular weight and block length ratios can be easily changed, which allows control of the size and morphology of the micelles. Functionalization of block copolymers with cross linkable groups can increase the stability of the corresponding micelles and improve their temporal control. Substitution of block copolymer micelles with specific ligands is a very promising strategy to a broader range of sites of activity with a much higher selectivity.

Advantages of polymeric micelle over monomeric micelle:

Polymeric micelles, which are either formed from block copolymers by ionic or by hydrophobic interactions have several advantageous features that make them interesting as drug delivery systems. Some of them mention below:

1) Polymeric carriers might lead to precipitation in water, since the drug-polymer interaction can result in conversion of functional water-soluble groups of the drug into more hydrophobic groups.

2) Polymeric micelles refer to the easy for sterilization via filtration and safety for administration.

3) Some polymeric micelles seem to present better solubilization capacity when compared to surfactant micelles due to the higher number of micelles and/or larger cores of the formers.

4) The slow dissociation of kinetically stable polymeric micelles allows them to retain their integrity and perhaps drug content in blood circulation above or even below the CMC for some time, creating an opportunity to reach the target site before decaying into monomers.

5) Well defined core shell architecture. For example, the core of amphiphilic block copolymer micelles is capable to accommodate (solubilize) poorly water soluble drugs that are otherwise difficult to administer to the body. The hydrophilic shell provides colloidal stability to the whole assembly.

6) Small size (< 150 nm). Since the smallest blood vessels in the body (the capillaries) have a diameter of approx. 200 nm, polymeric micelles are able to freely circulate in the blood stream after injection of the drug solubilisate.

7) High physical stability. Because the critical micelle concentration (CMC) of a block copolymer can be several orders of magnitude lower than that of a classical surfactant, the micelles are highly resistant against dilution that unavoidable when administered to the patient (e.g. by injection).

Critical micelle concentration: ^22-25

Critical micelle concentration (CMC) is defined as the concentration of surfactants above which micelles are spontaneously formed.²² Upon introduction of surfactants (or any surface active materials) into the system they will initially partition into the interface, reducing the system free energy by (a) By lowering the energy of the interface (b) By removing the hydrophobic parts of the surfactant from contacts with water.

Subsequently, when the surface coverage by the surfactants increases and the surface free energy (surface tension) decreases and the surfactants start aggregating into micelles, thus again decreasing the system´s free energy by decreasing the contact area of hydrophobic parts of the surfactant with water. Upon reaching CMC, any further addition of surfactants will just increase the number of micelles (in the ideal case).

There are several theoretical definitions of CMC. One well-known definition is that CMC is the total concentration of surfactants under the conditions:

If C = CMC, (d³F/dC_t³) = 0

F = a [micelle] + b [monomer]: function of surfactant solution

C_t: total concentration

a, b: proportional constants

Therefore, CMC depends on the method of measuring the samples, since a and b depend on the properties of the solution such as conductance and photochemical characteristics.

When the degree of aggregation is monodisperse, the CMC is not related to the method of measurement. On the other hand, when the degree of aggregation is polydisperse, CMC is related to both the method of measurement and the dispersion. CMC is an important characteristic of a surfactant. Before reaching the CMC, the surface tension changes strongly with the concentration of the surfactant. After reaching the CMC, the surface tension stays more constant. CMC is the concentration of surfactants in the bulk at which micelles start forming. The word BULK is important because surfactants partition between the bulk and interface and CMC is independent of interface and is therefore a characteristic of the surfactant molecule.

In most of the situations like for e.g. in surface tension measurements or conductivity measurements, the amount of surfactant at the interface is negligible compared to that in the bulk and CMC is approximated by the total concentration as is done in most of the textbooks.

There are important situations where interfacial areas are large and the amount of surfactant at the interface cannot be neglected. For example if we take a solution of a surfactant above CMC and start introducing air bubbles at the bottom of the solution, these bubbles, as they rise to the surface, pull out the surfactants from the bulk to the top of the solution creating a foam column thus bringing down the concentration in bulk to below CMC. This is one of the easiest methods to remove surfactants from effluents (foam flotation). Thus in foams with sufficient interfacial area there will not be any micelles. Similar reasoning holds for emulsions.

Factors affecting CMC and micellar size:

1) Nature of hydrophobic group-

For ionic amphiphiles, increase in the number of carbon atoms in an unbranched hydrocarbon chain tends to decrease CMC. CMC is halved when length of the hydrocarbon chain is increased by one methylene group but this relationship no longer holds beyond 16 carbon atoms. Further increase in carbon atoms shows no appreciable effect on CMC due to coiling of long chain in solution. For non ionic surfactants, increase in hydrocarbon chain length decreases CMC and addition of one methylene group decrease the CMC one third of its original value. Replacement of methyl group by trifluoromethyl group doubles CMC. Addition of phenyl ring to straight chain hydrocarbon shows equivalent effect on CMC as that of the effect shown by three and a half methylene groups. Substituent’s such as –Cl, -Br, -F ,-I , on the phenyl ring increase the hydrophobicity and thereby decreases CMC.

2) Nature of hydrophilic group-

For the non ionic surfactant, in case of polar group, the factor that controls the micellar size is-

i) The mean distance of the closest approach of the counter ion to the charged centre of the surfactant.

Eg- decylammonium bromide forms much larger micelle than decyltrimethylammonium bromide because bromide counter ions approach more closely towards the charged nitrogen atom of decylammonium thus shields the repulsive electric forces and forms large micelle.

ii) Solvent interactions -

Eg- Hydrogen bonding between oxygen atom of decylmorpholinium bromide and water is responsible for its smaller size micelle as compared to decylpiperidinium bromide which does not interact with solvent.

iii) Effectiveness of dielectric constant -

Eg-When ethyl group associated with polar head is replaced by ethanol group in compounds like decylethylammonium bromide or decyldiethylammonium bromide its aggregation number is increased due to change in effective dielectric constant produced when polar head structure is changed. Replacement of nitrogen by phosphorus or arsenic in decyltrimethylammonium bromide increases aggregation number by at least 20% and decreases CMC by 35%. Increase in the number of the ionized groups present in the surfactant higher CMC. Position of the ionic group affects the micellar properties. Eg-CMC of sodium alkyl sulphate increases when sulphate group moves from terminal site to medial position. For polyoxyethylated ether type non ionic surfactants, increase in polyoxyethylene chain length increases CMC because increase in polyethylene chain length tends to increase hydrophilicity.

3) Nature of the counter ion -

Counter ions associated with the ionic amphiphile have a pronounced effect on the micellar properties. With amphiphile drugs like mepyramine and bromopheniramine maleate containing pyridine ring; proton transfer interaction occurs between maleate counter ion and nitrogen of the pyridine ring as a result there is no clear CMC. Increase in the size of the counter ion tends to increase CMC value.

4) Effect of additives -

Addition of the electrolytes decreases the ionic atmosphere around the polar group as well as decreases the repulsion between them and thus decreases CMC. Most effective electrolytes causing lowering of CMC are nitrates of sodium and potassium. Lower alcohols when added to the ionic surfactants tend to decrease CMC but in case of non ionic surfactants; reason for this is decreased free energy of micelles due to diluted surface charge density on the micelles. Addition of water soluble alcohols like methanol or ethanol tend to increase CMC and this is due to the weakening of the hydrophobic bonds.

5) Effect of temperature -

Decrease in the CMC of the ionic surfactants with increase in the temperature at lower range is due to dehydration of the monomer further increase in temperature tend to disrupt structured water molecules around the hydrophobic groups which oppose micellization. Increase in the temperature tends to decrease the micellar size of the ionic surfactants and increase in temperature increases size of the polyoxyethylene non ionic surfactants. Increased temperature tends to extend polyoxyethylene chain thereby increase the amount of water physically trapped by the micelle.

6) Effect of pressure-

Effect of pressure on the CMC of alkyltrimethylammoniun bromide was studied by conductivity technique and it was found that up to 150Mpa there is increase in CMC followed by decrement at higher pressure. Such behavior is rationalized in the terms of solidification of the micellar interior and pressure induced increase in the dielectric constant of the water.

Thermodynamics of micelle formation: ^26-32

Thermodynamics of micelle formation can be explained by using two models

1. Phase separation approach:-

Micelles are considered to form separate phase at CMC.

a. Application to non ionic surfactant

∆Gm^φ⁼ 2.303RT [log cmc-log w].

∆Gm^φ=std free energy change for transfer of one mole of amphiphile from solutionto micellar phase.

b. Application to ionic surfactant

∆Gm^φ⁼ 4.606RT [log cmc-log w]

2. Mass action approach:

Micelles and unassociated monomers are considered to be in association-dissociation equilibrium.

∆Gm^φ⁼ RT log Xcmc

Xcmc=CMC expressed as mole fraction.

Mass action model can be considered as more realistic process than phase separation model.

Advantages of Micellization: ^{4, 6,}

(1)Incorporation of large quantity of hydrophobic drug - By using micelles we can incorporate essentially hydrophobic drug into the micellar core which is surrounded by hydrophilic groups thus it helps in increasing the solubility of the drugs having limited aqueous solubility.

(2) Increased chemical stability of drug- As micelles protect the hydrophobic drugs by their entrapment into the micellar core; they are supposed to increase the chemical stability of the drug by preventing their hydrolysis or enzymatic degradation.

(3) Increased efficacy of drug - Naturally as the drug is in the protective core of the micelles; it offers site specific delivery of the drug thereby increases efficacy of the drug.

(4) Taste masking-This is the important case with respect to the aesthetic properties of the drug. Drugs having essentially bitter taste can be effectively kept in the micellar core to mask its taste and thus it can be made aesthetic.

(5) Passive targeting- By keeping a hydrophobic drug in the micellar core we can locate the drug in the microorgans like arteries because the smallest artery in the body is larger than the micellar size hence micelles can easily enter the arteries.

Applications of Micellization:

1. Solubilization: ^33-39

Solubilization can be defined as ‘‘the preparation of a thermodynamically stable isotropic solution of a substance normally insoluble or very slightly soluble in a given solvent by the introduction of an additional amphiphilic component or components.’’ The amphiphilic components (surfactants) must be introduced at a concentration at or above their critical micelle concentrations. Simple micellar systems (and reverse micellar) as well as liquid crystalline phases and vesicles referred to above are all capable of solubilization. In liquid crystalline phases and vesicles, a ternary system is formed on incorporation of the solubilisate and thus these anisotropic systems are not strictly in accordance with the definition given above.

Solubilization by micelles Micelles resembles miniscule pools of liquid hydrocarbon surrounded by shells of polar head. They solubilize poorly water soluble drugs. Solubilization depends upon the chemical structure of solublizate. It does not occur below CMC. The location of a solubilized molecule in a micelle is determined primarily by the chemical structure of the solubilisate. Solubilization can occur at a number of different sites in a micelle:

1. On the surface, at the micelle–solvent interface

2. At the surface and between the hydrophilic head groups

3. In the palisades layer

4. More deeply in the palisades layer and in the micelle inner core.

Fig. 7: In aqueous systems - solubilization of drugs at diff. positions of micelle

Examples:

1. Polar alcohols are soluble in aqueous solution, so it located in solution / on surface of micelle.

2. Phenol are having polar –OH group and non polar benzene ring. In which –OH gr. Located in hydrophilic environment and benzene ring in hydrophobic environment, so it located at the surface and between the hydrophilic head groups.

3. Semipolar materials, such as fatty acids are usually located in the palisades layer, the depth of penetration depending on the ratio of polar to non-polar structures in the solubilisate molecule.

4. Non-polar additives such as hydrocarbons tend to be intimately associated with the hydrocarbon core of the micelle.

In non aqueous system-

Reverse micelles formed in non-polar solvent systems containing surfactant, polar additives may be solubilized in the core where a polar interaction of head groups occurs. A preferred location of the solubilisate molecule within the micelle is largely dictated by chemical structure. However, solubilized systems are dynamic and the location of molecules within the micelle changes rapidly with time. Solubilization in surfactant aqueous systems above the critical micelle concentration offers one pathway for the formulation of poorly soluble drugs. From a quantitative point of view, the solubilization process above the CMC may be considered to involve a simple partition phenomenon between an aqueous and a micellar phase. Thus the relationship between surfactant concentration Csr and drug solubility Cdss is given by following equation.

Cdss = Cdsa + P Cdsa. Csr

Where Cdsa is the drug solubility in the absence of surface active agent and P is the distribution coefficient of drug between the micelle and bulk phases. A plot of Cdss versus Cs is linear with a slope of P Cdsa, which is the solubilizing capacity of the micelle. The effect of altering the pH of the vehicle, in the case of a partly ionized drug will be to alter the apparent partition coefficient. Thus the effect of increasing the pH of a vehicle containing an acidic drug is to reduce the proportion of drug in the micellar phase. If the surfactant is a weak electrolyte, it may induce a concentration-dependent change in pH thus altering drug partitioning and solubility. In general the solubilizing capacity for surfactants with the same hydrocarbon chain length increases in the order anionic < cationic < non-ionic, the effect being attributed to a corresponding increase in the area per head group, leading to looser micelles with less dense hydrocarbon cores which can accommodate more solute.

The solubilizing capacity for a given surfactant system is a complex function of the physicochemical properties of the two components which, in turn, influence the location or sites where the drug is bound to the micelle. The molar volume of the solubilisate together with its lipophilicity is important factors, the former reducing and the latter increasing solubilization.

Many pharmaceutical products contain a number of solutes potentially capable of being solubilized within the micellar phase. Thus competition can occur between solutes resulting in an altered solubilizing capacity. Furthermore, the addition of a second highly solubilized component to form a mixed micellar system may greatly alter the structure, size and solubilizing capacity of the system, thereby greatly enhancing drug solubility.

Pharmaceutical Examples of solubilization:

· The solubilization of phenolic compounds such as cresol, chlorocresol, chloroxylenol and thymol with soap to form clear solutions for use in disinfection.

· Solubilized solutions of iodine in non-ionic surfactant micelles (iodophors) for use in instrument sterilization.

· Solubilization of drugs (for example, steroids and water insoluble vitamins), and essential oils by non-ionic surfactants (usually polysorbates or polyoxyethylene sorbitan esters of fatty acids).

2. Stabilization of the biphasic system-

Micelles formed by the surfactants tend to stabilize biphasic systems like emulsions by decreasing the surface free energy of the system.

3. Site specific drug delivery-

Micelles are able to give site specific drug delivery which is of prime importance in the areas like cancer treatment thus it also supposed to increase the bioavailability of the drugs. It is briefly discussed in following points.

Recent advances in micellar drug delivery system:

1. Multifunctional polymeric Micellar Nanomedicine for Cancer Therapy:

Polymeric micelles are supramolecular, core-shell nanoparticles that offer considerable advantages for cancer diagnosis and therapy. Their relatively small size (10-100 nm), ability to solubilize hydrophobic drugs as well as imaging agents, and improved pharmacokinetics provide a useful bioengineering platform for cancer applications. Several polymeric micelle formulations are currently undergoing phase I/II clinical trials, which have shown improved antitumor efficacy and reduced systemic toxicity.^40-42 This minireview will focus on recent advancements in the multifunctional design of micellar Nanomedicine with tumor targeting, stimulated drug release and cancer imaging capabilities. Such Functionalization strategies result in enhanced micellar accumulation at tumor sites, higher drug bioavailability as well as improved tumor diagnosis and visualization of therapy. Ultimately, integrated nanotherapeutic systems (e.g., theranostic Nanomedicine) may prove essential to address the challenges of tumor heterogeneity and adaptive resistance to achieve efficacious treatment of cancer. ^{43, 44.}

Cancer remains as one of the leading causes of mortality worldwide, and is responsible for approximately 13% of all deaths, according to world health organization.⁴⁵ Currently, the treatment options include surgical resection, radiation, and chemotherapy. However, although over 90 chemotherapeutic drugs have been approved by the FDA for clinical use, their efficacy has been severely hindered by dose-limiting toxicity and patient morbidity. Recently, nanoscale (10-200 nm) therapeutic systems have emerged as novel therapeutic modalities for cancer treatment. These systems include polymeric micelles, polymer-drug conjugates, dendrimers, liposomes and inorganic particulates. Compared to conventional small molecule-based therapy, nanotherapeutic systems have several potential advantages for cancer therapy, including higher payload capacity, prolonged blood circulation times, reduced toxicity to healthy tissues and improved anti-tumor efficacy. In this article, we will review key advances of one of these emerging nanotherapeutic systems, polymeric micelles and discuss their potential for cancer therapy.^46-48.

Polymeric Micelles: Properties and Advantages for Cancer Treatment-

The use of polymeric micelles for cancer treatment was first reported in the early 1980s by Ringsdorf and coworkers. These spherical particles are nanosized (typically in the range of 10-100 nm) supramolecular constructs formed from the self-assembly of biocompatible amphiphilic block copolymers in aqueous environments. In water, the hydrophobic portion of the block copolymer self-associates into a semi-solid core, with the hydrophilic segment of the copolymer forming a coronal layer. The resulting core-shell architecture is important for drug delivery purposes, because the hydrophobic core can act as a reservoir for water insoluble drugs, while the outer shell protects the micelle from rapid clearance. Although several functional aspects of the constituent blocks have been explored (e.g. temperature or pH sensitive blocks), the most important criteria are biocompatibility and/or biodegradability. Currently, the most commonly used corona-forming polymer is polyethylene glycol (PEG), with a molecular weight range from 2 to 15 kD. Core-forming blocks typically consist of poly(propylene oxide) (PPO), poly(D,L-lactic acid) (PDLLA), poly(ε-caprolactone) (PCL), and poly(L-aspartic acid) to name a few. Given their lipophilic nature, most anticancer drugs are inherently water insoluble. As an example, paclitaxel, a highly effective anticancer agent that inhibits microtubule growth by binding to the β subunit of tubulin, has a water solubility of 0.0015 mg/mL. While this degree of hydrophobicity is favorable for drug permeation through cell membranes, intravenous (i.v.) administration would result in rapid drug aggregation and formation of capillary embolisms. By encapsulation of the drug within the hydrophobic core of the micelle, the apparent solubility of the drug can be significantly increased. For example, micelle encapsulation of paclitaxel increased the solubility over three orders of magnitude from 0.0015 to 2 mg/mL. Hence, polymer micelles allow for the in vivo use of previously existing drugs otherwise deemed too hydrophobic or toxic, without having to manipulate the chemical structure of the agent. Additionally, encapsulating the drug within the polymer core affords drug stability by hindering enzymatic degradation and inactivation.

The hydrophilic micellar corona also plays an important role in in vivo applications by reducing particle recognition by opsonin proteins. In the absence of this brush-like coating, the micelle would undergo rapid phagocytic clearance by the reticuloendothelial system (RES). Additionally, the critical micelle concentration (CMC, the concentration threshold of polymers at which micelles are formed) is very low for polymeric micelles, typically on the order of 10⁻⁶-10⁻⁷ M, resulting in stable constructs that are not easily dissociable in vivo. These characteristics together contribute to longer blood circulation times, and this longevity results in an increase in the bioavailability of the drug. The long circulation times and small size of polymer micelles also aid in the preferential accumulation of micelles in tumor tissue through the enhanced permeability and retention (EPR) effect, which allows for passive targeting due to fenestrations between endothelial cells in angiogenic tumor vessels.^46-52.

These polymeric micelles act by following path-

1. Enhancement in solubility-

Polymeric micelles provide a unique and complementary nanoplatform to the above nanosystems for drug delivery applications. The hydrophobic cores of micelles provide a natural carrier environment that allows easy encapsulation of poorly soluble anticancer drugs. The non-covalent encapsulation strategy makes it feasible to entrap drugs without the requirement of reactive chemical groups. Meanwhile, the unique chemistry of the polymer constituents does allow for the chemical conjugation of anticancer drugs, such as doxorubicin, to these chains, effectively enhancing drug loading and hindering premature drug release upon administration. Additionally, the size of polymeric micelles, 10-100 nm, can be easily controlled by varying the hydrophobic block of the amphiphilic copolymer. This size range also permits for evasion of renal filtration while allowing for increased tumor penetration compared to liposomes. ^{41, 53, 54.}

2. Site specificity-

Active targeting strategies, which involve the functionalization of the micelle surface with a ligand that recognizes tumor-specific receptors, are an intense area of study with several potential advantages. These include increased accumulation at tumor sites as well as increased uptake into cancer cells via receptor-mediated endocytosis. Commonly used ligands are grouped into the following classes: small organic molecules, peptides, carbohydrates, monoclonal antibodies, and DNA/RNA aptamers.

An example of a small organic molecule for cancer targeting applications is folic acid, whose receptor is over-expressed (100-300 times) in a variety of tumors. Park and coworkers functionalized DOX-containing PEG-PLGA micelles with folic acid and were able to show significantly increased uptake and cytotoxicity in KB cells In vivo studies showed that folate-labeled micelles led to a 2-fold decrease in tumor growth rate compared to non-targeted micelles. Peptides are also actively explored as ligands for tumor-targeted drug delivery. Recent work by our laboratory has investigated the use of cyclic (Arg-Gly-Asp-D-Phe-Lys) (cRGDfK) peptide, which targets the α_vβ₃ integrin over expressed on the surface of angiogenic tumor vessels.

Carbohydrate molecules, such as galactose and lactose, have also been used to functionalize micelles. These ligands have high affinity for the asialoglycoprotein receptor (ASGPR) over expressed in hepatocellular carcinoma. A galactose-labeled poly(ethylene glycol)-co-poly(γ-benzyl L-glutamate) block copolymer was used by Cho and coworkers to produce micelles encapsulating paclitaxel, and exhibited a 30% increased uptake in ASGPR cells. Monoclonal antibodies represent another wide class of active targeting ligands. Recently, Torchilin and coworkers reported diacyllipid-PEG (PE-PEG) micelles conjugated with an anti-cancer monoclonal antibody (mAb 2C5) or an anti-myosin mAb 2G4 antibody to target lung cancer cells. Micelles encoded with 2C5 were able to increase paclitaxel accumulation (four-fold after 2 h) and cytotoxicity in lung tumors over control micelles. Finally, tumor-specific aptamers, DNA or RNA oligonucleotides identified by library screening, are also gaining potential as targeting ligands. Docetaxel-loaded PEG-PLGA micelles were recently conjugated with an RNA aptamer specific for the prostate specific membrane antigen (PSMA) to treat prostate tumors. In vivo studies in LNCaP xenografts showed overall increased anti-tumor efficacy and lesser systemic toxicity than non-targeted micelles and more importantly, total tumor regression in five of seven mice was reported.^{55, 56.}

3. Stimulated release of therapeutics-

Upon entering the tumor site, it is desirable that the therapeutic agent be released from the micelles in a controlled fashion in order to reach cytotoxic levels. To achieve this, several strategies have been explored that include pH-, temperature-, and ultrasound-stimulated release.

It is now well known that tumor tissues tend to have lower pH values (as low as 5.7) than normal tissue environments (pH 7.4), due to the glycolysis metabolism of cancer cells. Additionally, the process of endocytosis or the sequestration of the nanocarriers into vesicles (e.g. late endosomes, and heavily degradative lysosomes) is one associated with low pH values of ~5.0-5.5. Hence, changes in pH values encountered by micelles upon intravenous injection provide a possible venue through which to achieve stimulated release of drugs. Two different strategies have been reported to induce pH-sensitive release of drugs from micelles. These include the use of acid-labile bonds and non-covalent strategies involving selective protonation of pH-sensitive components inside the micelle. In the first strategy, Kataoka and coworkers were able to formulate micelles where doxorubicin was conjugated to the PEG-pAsp copolymer via a hydrazone linkage. The resulting micelles had high loading of DOX (42.5%) and pH sensitive release; 3% of the drug was released after 48 h in pH 7.4 and 25% release of drug was achieved at the same time at pH 5.5. In vivo studies showed increased tumor accumulation, greater tolerance for the drug and tumor regression in 50% of mice. Non-covalent strategies for pH-sensitive release were explored by several groups. For example, Tang et al. devised a triblock polymer of PEG, poly (2-(dimethylamino) ethyl methacrylate) (DMA), and poly (2-diethylamino) ethyl acrylate (DEA) resulting in a system that dissolves completely in acidic solution but forms micelles at high pH (pH 8.0). Acid sensitive release of dipyridamole was observed with a 50% increase of drug release at pH 3.0 over that at pH 7.4. ^{57- 61}

Technologies that permit for site-specific elevation of temperature have led to the development of heat-sensitive polymer micelles. The polymer of choice is poly (N-isopropylacrylamide) or pNIPAM, which has a lower critical solution temperature (LCST) of 32 °C. Okano and coworkers reported micelles where poly (butyl methacrylate) (PBMA) was used to form the hydrophobic core while pNIPAM was used as the thermosensitive corona. The resulting pNIPAM-b-PBMA micelles were loaded with DOX and released 15% of the drug after 15 h at 30°C, compared to 90% release in the same time period at 37°C. Cytotoxicity experiments showed less than 5% cell death at 29°C, but 65% cell death at 37°C.

Presently, ultrasound is used to trigger drug release from drug delivery systems through mechanisms that include local temperature increase, cavitation which increases the permeability of cell membranes, and the production of highly reactive free radical species which can accelerate polymer degradation. Pitt and coworkers designed ultrasound-sensitive pluronic micelles containing doxorubicin. Following stabilization of these pluronic micelles with PEG-phospholipid (PEG-DSPE), in vivo experiments showed that ultrasound was able to improve the antitumor efficacy of both free DOX and micelle incorporated DOX, with ultrasound delaying tumor growth significantly longer over micelles without ultrasound.^62-65.

Thus unique architecture of polymeric micelles allows for the incorporation of multiple functional components within a single micelle. By combining tumor targeting, stimulated release of therapeutics, and the delivery of imaging agents, multiple interventions against a tumor can be integrated into one platform. Such a ‘theranostic’ entity has been defined as a Nanomedicine platform that can diagnose, deliver targeted treatment in a controlled manner, and monitor response to cancer therapy.

2. Ultrasonic-Activated Micellar Drug Delivery for Cancer Treatment-

The high toxicity of potent chemotherapeutic agents limits the therapeutic window in which they can be utilized. This window can be expanded by controlling the drug delivery in both space (selective to the tumor volume) and time (timing and duration of release) such that non-targeted tissues are not adversely affected. Research in this area has focused on the synthesis of different drug depots that are capable of delivering a high concentration of chemotherapy drugs to cancerous tissues without affecting cells and organs in the systemic circulation. These depots can be broadly classified into three groups: liposomes, micelles and shelled vesicles. In this review we focus on the use of micelles in conjunction with ultrasound (US) to treat cancerous tissues. Low frequency ultrasound refers to frequencies less than 1 MHz, while the ranges for medium and high acoustic frequencies are 1-5 MHz and 5-10 MHz, respectively. We will present the advantages and disadvantages of such a drug delivery system, the recent advancements in this field, the future directions, and some unanswered questions that remain in this research topic; but first we will discuss the advantages of ultrasound.

The mechanisms of this acoustically activated micellar drug delivery system are still under investigation, and in vitro there is a strong correlation with insonation frequency and power density that suggests a strong role of cavitation. Here we will discuss the two main mechanisms that render this micellar drug delivery system effective. Ultrasound appears to disrupt the core of polymeric micelles, allowing the drug to be released in the volume of the ultrasonic field. Additionally, ultrasonic waves have been shown to cause the formation of micropores in cell membranes, which in turn allows for the passive diffusion of drugs into cell.^{66, 67, 70}

Disruption of micelles:

After proving that Dox and Rb were released from micelles under the action of ultrasound, Husseini et al. embarked on a study of the mechanism underlying this release. They improved their previously designed ultrasonic exposure chamber with fluorescence detection so as to record acoustic emissions at 70 kHz while simultaneously recording the decrease in fluorescence. This in vitro study showed that there is a threshold value of about 0.38 W/cm² below which no measurable release occurred. Furthermore the onset of Dox release from P105 micelles corresponded to the emergence of a subharmonic peak in acoustic spectra at this same threshold. The existence of a threshold at this intensity tends to point toward a strong role of cavitation, particularly inertial or collapse cavitation, in this release phenomenon. Several groups have reported the existence of a threshold for the onset of inertial cavitation. ^{68, 69}

Several publications have reported ultrasonic intensity thresholds for an observed biological effect in cells and tissues Mitrogotri et al. were the first to show the existence of an ultrasonic threshold for enhancing skin permeability. This threshold is a strong function of ultrasound frequency; as the frequency increases so does the threshold. Tang el al. showed that low-frequency sonophoresis (LFS) was able to permeabilize pig skin using 20 kHz ultrasound.⁷¹ They postulated that the key mechanism involved in LFS is cavitation bubbles induced by US. Copious research has been conducted on increased cell membrane permeability under the action of ultrasound For example; there is a reported threshold for DNA delivery to rabbit endothelial cells of about 2,000 W/cm² at a pulse average intensity 0.85 MHz (short pulse average intensity). Another example is the threshold of 0.06 W/cm² at 20 kHz reported by Rapoport et al. for HL-60 lysis. The range reported for biological thresholds is obviously very large, and thus provides little guidance for a priori prediction of threshold values for biological events. One must remember that in biological systems, the observed event is not the threshold of inertial cavitation; there is usually an ultrasonic intensity beyond the simple inertial cavitation threshold that is required to provide sufficient numbers and sufficient intensities of damaging cavitation events. Biological systems are much more complicated. In addition to the experimental factors mentioned above (e.g., level of gas saturation and heterogeneous nucleation materials), one must also consider the cells involved. For example, biological manifestations will be related to things such as the proximity of the cells to the collapse events, the presence of microjets from collapse events, the cell membrane strength and integrity, the requirements following cell membrane permeation (transport only to the cytosol or all the way to the nucleus) to produce a biological response, and much more. Obviously, much research remains to be done in this area of predicting thresholds for cellular response.

In this review, we will devote some discussion to the origin of the subharmonic acoustic peak, inertial cavitation, and its relation to the release phenomena. As bubbles oscillate with increasing amplitude in an ultrasonic field (of frequency f), they start to generate higher harmonic (2f, 3f, etc.), ultraharmonic (3/2 f, 5/2f, etc.), and subharmonic (f/2, f/3, etc.) emissions. There are reports that correlate the subharmonic emission with certain indicators of inertial cavitation, including sonoluminescence, acoustic white noise, and iodine generation. Leighton used mathematical modeling of cavitating bubbles to simulate a signal at f/2 (the subharmonic) and came to the conclusion that a subharmonic occurs due to a prolonged expansion phase immediately preceding a delayed collapse phase of the bubble implosion even. However, modeling by others show that the f/2 signal can be produced (mathematically at least) without collapse cavitation occurring, albeit the definition of “collapse” is difficult to define in a mathematical model.

Also the membrane permeability of 3T3 mouse cells correlates with an increase in background noise in acoustic spectra. The group came to the conclusion that ultrasound-induced permeabilization of cell membranes is caused by collapse cavitation events. On the other hand, Liu et al. found a strong dependence of the degree of hemolysis (permeabilization of red blood cells as measured by the degree of hemoglobin release) on the intensities of the subharmonic and ultraharmonic frequencies, but not on the broadband noise The group concluded that the best correlation between ultrasonic parameters and hemolysis was the product of the total ultrasonic exposure time and the subharmonic pressure. Accordingly, there are varied opinions as to whether the subharmonic emission always correlates with biological phenomena, or even with collapse cavitation.

As to the relationship between the mechanism of release and inertial cavitation, Husseini et al. postulated that as the shock wave caused by collapse cavitation propagates through the vicinity of a micelle, the abrupt compression and expansion of fluid in the shock wave is able to shear open the micelle so that the drug is released or at least exposed to the aqueous environment. Oscillating bubbles, even in stable cavitation, create very strong shear forces near the surface of the bubble. The shearing velocity of fluid near a 10 micron (diameter) bubble, with a 1 micron oscillation amplitude and 70 kHz oscillation frequency is approximately 1 m/s Additionally, it important to keep in mind that the extremely high viscous shear rates near the surface of 10-μm bubbles are on the order of 10⁵ sec^-1. Furthermore, this rate is equivalent to shearing water in a 1 mm gap between parallel plates in which plate is stationary and the other moving at 100 m/s. Thus, the group speculated that these shear forces may be strong enough to open up a P105 micelle, exposing the hydrophobic drug inside its core to the surrounding aqueous environment.

The group also extended their study of the release mechanism to stabilized and unstabilized micelles. In this study they compared the release of Dox from the core of unstabilized Pluronic^® 105 micelles to the release from stabilized micelles such as NanoDeliv™ micelles and micelles of pENHL described previously in section 3. They found that the release of Dox at 37 °C from Pluronic^® micelles appeared to be several times higher than the release from the more stabilized micelles. Interestingly, the onset of release occurred at about the same power density for all carriers investigated in their study, whether stabilized or not. Similarly, the threshold of Dox release from all three micelles correlated with the emergence of subharmonic peaks in the acoustic spectra. Apparently the structures of the stabilized and non-stabilized micelles are perturbed by cavitation events that cause the release of Dox. The group hypothesized that stabilized micelles are less susceptible to disruption by the shearing forces of shock waves produced by cavitation events since the threshold of release also correlates with the subharmonic peak in all micellar systems investigated, discovering the origin of the subharmonic peak is vital in understanding drug release from micelles under the action of ultrasound. ^72-77

Disruption of cell membrane:

Although Pitt's group has focused on studying the possible mechanisms by which the P105 micelles and ultrasound drug delivery system induce drug uptake by the cancer cells, is has also studied the biological mechanism involved here. The comet assay was used to quantify the amount of DNA damage in HL-60 cells by measuring the fraction and length of broken nuclear DNA strands. Large amounts of DNA damage as measured by the comet assay are indicative of cell death, either by necrosis or by apoptosis ¹⁸. Results of the comet assay show that Dox eventually binds to the DNA and causes it to fragment. In a separate but related study, Husseini et al. reported on the mode of cell death exhibited by cells exposed to a combination of Pluronic^® micelles, ultrasound and Dox. Using the comet assay, the group observed the electrophoretic pattern of the nuclear DNA from HL-60 cells insonated at 70 kHz in a solution of P105 micelles containing 10 μg/ml Dox for 30 minutes, 1 hour and 2 hours. The pattern of the DNA fragments as well as the gradual damage observed after two hours of ultrasonic exposure were consistent with apoptosis as a mode of cell death rather than necrosis. However, the question remains as to if and how ultrasound enhances uptake of Dox by the cell. In this section, we will discuss three postulated mechanisms that have been tested in an attempt to answer the above question. These mechanisms are 1) ultrasonic release of the drug from micelles is followed by normal transport into the cell; 2) ultrasound upregulates endocytosis of the micelles (with drug) into the cell; 3) ultrasound perturbs the cell membrane which increases passive transport of the drug and Pluronic^® molecules into the cell.^{68, 69, 72-74}

The first hypothesis proposes that the drug is released from micelles outside the cancer cells, followed by normal penetration of the polymer and drug into the cells by simple diffusion or normal cellular uptake mechanisms. To test this postulated mechanism, the hydroxyl groups at the ends of P105 chains were labeled with a fluorescein derivative. HL-60 cells were then incubated or sonicated with the fluorescein-labeled P105 micelles containing Dox, which fluoresces at a different wavelength. Results showed that Dox in 10 wt % P105 appeared inside the cells.

The next question was whether the fluorescently-labeled P105 entered the cells along with or independent of the Dox. The experiments revealed the presence of P105 inside the cells when incubated or insonated for 20 minutes. Because the labeled P105 molecules themselves were found inside the HL-60 cells, they rejected the first hypothesis of external drug release followed by passive drug diffusion without the polymeric diffusion into the cells. Although their experiment showed that the P105 entered the cells, it was not possible to determine whether the copolymer entered the cells through holes punched in the cell membrane or through endo-/pino-cytotic routes.

Next they turned their attention to the second hypothesis whereby entire micelles (with drug) are endocytosed into the cells. Since it is unlikely that HL-60 cells express a receptor for Pluronic^® micelles, receptor-induced endocytosis was considered to be very unlikely. However, pinocytosis involves vesicles that nonspecifically engulf small volumes of extracellular fluid and any material contained therein. To test the postulate that the cells were taking up the drug and P105 in by endocytosis, a model drug that fluoresces more strongly in acidic environments was used, namely Lysosensor Green. This probe has a pKa of 5.2, which causes it to fluoresce more strongly in an acidic compartment such as a lysosome. The great majority of endosomes fuse with a primary lysosome to form a secondary lysosome, which has a pH of about 4.8 while the pH outside these compartments is about 7.1. Cells exposed to US and P105 micelles with Lysosensor Green were examined by flow cytometry, which showed no difference in fluorescence between cells incubated and insonated for 1 hour at 70 kHz. Thus, ultrasonic exposure did not cause the probe to partition to a more acidic environment anymore than it did without ultrasound, and the hypothesis was rejected that US induces upregulation of endo-/pino-cytosis. The observation that US enhanced the uptake of both drug and labeled Pluronic^® supported the third hypothesis that drug-laden micelles entered through holes in the membranes of insonated cells in these studies. It is relevant that Rapoport et al. reported that US-assisted micellar drug delivery enhances the rate of endocytosis into cells.^70,71,78

3. Micellar Nanoparticles: Applications for Topical drug delivery

This is used to deliver API locally in an efficient manner. This concept is explained by using acyclovir which is an antiherpes agent. Commercially available acyclovir product - Zovirax which is to be applied for 5to7 times a day for 4–7 days. Comparative investigations were done with zovirax and MNP (for topical drug delivery).It was found that the amount of drug retained within skin was twofold higher for MNP than zovirax.

FUTURE PROSPECTUS:

Development of micellar syrup-

Current research is going on the development of the vitamin micellar syrup with the aim of increasing the absorption of the vitamins as well as to reduce the dose frequency. Use of biodegradable polymers in formation of micelle for targeted drug delivery system. The agents that have been encapsulated in nanoparticles for ultrasonic delivery have been primarily hydrophobic drugs. Future work includes other drug delivery vehicles having hydrophilic volumes and is able to sequester and deliver hydrophilic drugs. Development of core-crosslinked micelles in order to enhance in vivo stability.

CONCLUSION:

Micelles are dynamic structures having polar head and non-polar tail. They are formed from monomers. They can be normal phase micelles or reverse phase micelle. Distribution and orientation of drug in micelle depends upon hydrophilicity or hydrophobicity of the drug. Micellization has a prime role in solublization of the essentially insoluble drug as it tends to encapsule those insoluble drugs into partially aqueous environment. Block copolymers which are formed by the hydrophilic as well as hydrophobic blocks are used to form micelles shows enhanced efficacy in targeted drug delivery system. Currently polymeric micelles are enjoying topmost position in micellar drug delivery system mainly in the case of delivery of the chemotherapeutic agents. They increase the solublization of the drug; actively target them as well as release the drug in the stimulus response manner. In addition to this they are also used as diagnostic agents in cancer treatment. Thus many of the advantages related to drug delivery in cancer are integrated in a single platform of polymeric micelle hence they are popularly termed as multifunctional nanomedicinal systems.

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Received on 10.07.2014 Modified on 22.07.2014

Res. J. Pharm. Dosage Form. and Tech. 6(4):Oct.- Dec.2014; Page 267-281