COLLOIDOSOMES: A POTENTIAL DRUG DELIVERY SYSTEM

About Authors:
AMOL D.GHOLAP^*1, DATTATRAY TUPE²
¹ Department of Pharmaceutics, Vamanrao Ithape D. Pharmacy College, Velhale, Tal- Sangamner, Dist- Ahmednagar, MS-422605, India.
² Department of Regulatory Affairs, Lupin Limited, Kalina,
Santakruz (E), Mumbai, MS, India-400098.
*amolgholap16@yahoo.com

Abstracts
There are several newer lipid based systems are evoked and utilized now a days as dryg delivery systems like liposomes, transferosomes, ethosomes etc which provides effective solutions for problem regarding insolubility, instability, rapid degradation along with has wide application in the specialized area consisting protein delivery, targeting to the brain, and tumor targeting. This lipid based systems also utilized in for gene delivery with efficient performance while in this field the colloidosomes evoked as potential tool based on the vascular drug delivery system. There are several applications of vascular systems are present including reduction in the cost of therapy via improved bioavailability of medication generally in the case of poorly soluble drugs. The colloidosomes have several beneficial advantages like greater encapsulation efficiency with wide control on the size along with permeability and compatibility. The colloidosomes also have effective mechanical strength.

Reference Id: PHARMATUTOR-ART-1438

INTRODUCTION
The vesicular drug delivery systems utilized for an efficient tool for drug delivery directly to the site of action which induce reduction of drug toxicity along with no adverse side effects. These systems provide the reduction regarding the cost of therapy through improvement of bioavailability of medication as in the case of poor soluble drugs. The several other vascular drug delivery systems were evoked from past some decades consist of liposomes, transferosomes, ethosomes, niosomes etc. These systems are utilized to delay the drug elimination of rapidly metabolize drugs so that it functioned as a sustained release systems. These systems also help to counter several other problems in drug delivery like instability, rapid degradation and have wide application in the different drug delivery like gene delivery, protein delivery, brain targeting and targeting of tumor. ^1-4 The several other novel technology has been show great promises in the delivery of nutraceuticals and bioactives compounds. In this field recently the colloidosomes is evoked which utilized widely as a advanced tool for encapsulation of several materials like drugs, dyes, cosmetics, biomaterials as filler in the case of catalysis along with waste material.⁵

The capsules are fabricated by the utilization of self assemble of colloidal particles on to the interface of emulsion droplet which made colloidosomes hollow, elastic shells as shown in fig. no. 1. The permeability along with elasticity of colloidosomes can be controlled while the colloidosomes is new class of microcapsules. The colloidosomes generally consist of coagulated or fused colloid particles like a shell at interface of emulsion droplet articles which get self assemble on the surface of droplets in order to diminish the total interfacial energy forming colloidosomes. The several other types of colloidosomes like hairy colloidosomes consist of shell include the micro rod particles which are designed and fabricated novel colloidosomes capsules. Such capsule includes the aqueous gel core along with shells of polymeric micro rods and which formed with the help of Templating water-in –oil emulsions. This emulsions is stabilized through the rod like particles followed by gelling of the aqueous phase then dissolution of oil phase in ethanol along with redispersion of obtained colloidosomes microcapsules inside the water. Such nonspherical capsules can be utilized to store a large amount of encapsulated materials as compared to that of spherical capsules.

Fig: 1 The scanning electron microscope image of a colloidosomes.

POTENTIAL BENEFITS OF COLLOIDOSOMES
Size: It allows flexibility in applications along with the choice of encapsulated materials.

Permeability: It allows selective along with controlled release pattern.

Mechanical strength: It allows yield stress which helps to withstand several varying nature of mechanical loads along with that it enables release via defined shear rates.

Compatibility: It allows encapsulation of fragile along with sensitive ingredients like biomolecities and cells.

Advantages
It provides the efficient encapsulation of several active ingredients like drugs, proteins, vitamins, flavors, gas bubbles along with even living cells which utilized as functional foods to drug delivery for several biomedical applications. It provides a better advanced tool for nutrient along with drug delivery along with higher encapsulation efficiency. One of the possibility is that one can done immune isolation of living cells via encapsulation in colloidosomes which can acts as rigid scaffold that supports the living cell along with that it provides the protection from the immune system. It also allows the free diffusion of gases along with nutrients. The colloidosomes encapsulating cells provides the several advantages as that of bioreactors. The several food stuffs, fragrance along with active ingredients can be encapsulated effectively with the help of colloidosomes. It allows the rapid permeation of small macromolecules by forming templates for tissue growth by providing one type of protected enviourment with the help of three dimensional architecture. The enhancement in the viability of the cells can be achieved by fabrication of colloidosomes as a rigid porous super structure.

Limitations
One of the major problems in the colloidosomes manufacture is that it’s having poor yield of particles while its shell locking is not sufficient and hence the colloidosomes get coalesce and fall apart on transfer via water. The colloidosomes get losted when they are transfer from organic to water media. ⁶

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Core material
The core material can involve the polymer gel which includes the cross linked network of long polymer molecules along with that it provides sufficient physical strength. The base of gel can consist of water for example hydrogel and or organic liquids along with that the hydrogel provides the swelling and deswelling in water media. The gel consist of formation of spherical particle or ovoid particle or cylindrical particle or some kinds of three dimensional shaped particle. The gel particle consist of at least one dimension that is microns to millimeters in size while the particles size of the core material is dependent upon the intended application of the resultant colloidosomes. Usually the core material is in the range of about one or more microns to millimeters while several conventional methods like Microfluidics techniques, precipitation polymerization techniques along with suspension polymerization technique is utilized for the preparation of core particle. ^7-9 The gel having several properties like electrical charges, magnetic materials which attract the colloidal particles towards the core for example the magnetic materials attract the magnetic metal particles that serve as the colloidal particles.

There are several other factors which affect the property of gel or core material consists of external stimulus, temperature, pH along with electrical effects.

Colloidal particles
The several other materials like metal, a semiconductor, a polymer, an inorganic material, nanometer sized particles along with microsized particles can be utilized as colloidal particles while the colloidal particles having size smaller than that of core material. The core material involve the active interaction with that of colloidal particles with the help of electrical charges or magnetic properties of them. The nature of colloidal particles is negative charge when the there is positive charge core material is utilized. The following are several types of colloidal particles are used for examples
1.      Semiconductor colloidal particles consist of silicon, germanium, gallium arsenide and cadmium selenide.
2.      Polymer colloidal particles consist of polystyrene, polymethyl methacrylate, poly (lactic acid) along with poly (lactic acid-co-glycolic acid)
3.      Inorganic colloidal particles consist of gold, silver, copper, cobalt, palladium, platinum, manganese-zinc, silica, titania, iron oxide, nickel oxide etc.
4.      The magnetic colloidal particles consist of gold, silver, copper, iron oxide, nickel oxide, cobalt etc.
5.      The several other additional properties can possess inside them like fluorescence which utilized for chemical along with biological for example the colloidal particles can be sensitive to several diagnostic tools like MRI, ultrasound, X-ray etc. which determine the locations of them in body.

Classification of Colloidosomes
Depending upon the emulsion base utilization the colloidosomes are classified as water-in-oil emulsion based colloidosomes, oil-in-water based colloidosomes. Water-oil-water emulsion based colloidosomes. The colloidosomes can be classified depending upon the colloids nature like aqueous or oily gel core colloidosomes, hairy colloidosomes, nanoparticle colloidosomes, layer by layer colloidosomes along with nano-spherical colloidosomes.

METHOD OF PREPARATION OF COLLOIDOSOMES
Preparation of emulsion based colloidosomes
The water-in-oil emulsion is prepared by emulsification of aqueous solution in oil in the presence of colloidal particles while in this particles get adsorbed on the surface of the droplets which induce reduction of surface energy. By addition of polycations these particles get locked with the Vander Waals forces or through sintering the particles. These colloidal particles help for induction of proper stabilized water-in-oil emulsion. ¹⁰ After that the water-in-oil based colloidal dispersion is produced and there are two different methods are available to transfer them in to the water i.e. via centrifugation approach or by filteration approach. In the centrifugation method the obtained colloidal dispersion is further diluted with non aqueous phase containing ethanol or dodecane then it get centrifuged to separate them from that of supernatant. At last the obtained water core colloidosomes are washed with the help of ethanol along with water and get redispersed inside the water. The other approach that is filteration consist of filtering the oil suspension on the hydrophobic milipore membranes which further get added by water consist of small proportion of ethanol which added to top of the membrane thus removing the oil interface and resuspending the colloidosomes inside the water. This water-in-oil based colloidosomes can act as excellent encapsulating agent for the drugs, fragrances due to their mechanical resistant shell, the tunable porosity and better mass transfer ability because of absence of chemical barrier. ¹¹

Oil-in-water emulsion based colloidosomes
In this method oil is emulsified inside the aqueous solution consist of particles in the presence of a surfactant to induce oil-in-water emulsion. Such type of colloidal particles in the presence of surfactant is utilized to stabilize the oil/water interface. In this type an electrostatic driving force in includes which takes the colloidal particles to the emulsion interface and further the oil-in-water emulsion based colloidosomes dispersion is produced which added by ethanol or any other non aqueous phase. This later get centrifuged to separate them from that of supernatant while the obtained oil core colloidosomes are get washed by using ethanol and later redispersed inside the water.

Water-oil-water emulsion based colloidosomes
In this method a pendant drop of an aqueous suspension of latex particles is induced in an oil phase and which includes adsorption of closely packed particle monolayer on drop surface with the help of multiple infusion and withdrawal of the particle suspension via the capillary inside the oil phase. At last the pendant water drop in oil, densely coated with adsorbed particles is transferred by using a plannar oil-water interface to form a giant pendant colloidosomes involving a spherical water/oil/water film supported through latex particles which possibly bridging both surfaces. ^12-13 The water-in-oil-in-water double emulsion templates is applied for production of nanoparticle colloidosomes which having selective permeability. ¹⁴

Preparation of colloidosomes depending upon the nature of colloids
In this method a hot aqueous solution of agarose is emulsified in oil in the presence of solid particles to induce water-in-oil emulsion which is stabilized through solid particles while the system is cooled to set the agarose gel. The suspension of aqueous gel microcapsules is further diluted by using ethanol and centrifuged to separate them from the supernatant. Then the microcapsules is washed by using ethanol along with water and again redispersed inside the water which allows the formation of giant colloidosomes microcapsules having diameter from several tens to several hundreds of micrometers. By changing the size of the solid particles the average size of the colloidosomes can be varied.

Hairy colloidosomes
The basic concept in this method consists of three steps. First the hot aqueous solution of agarose is get emulsified inside the oil in the presence of polymeric particles which is rod shaped to induce a stable water-in-oil emulsion which is stabilized with the help of solid particles and further the system is cooled off to set the agarose gel. The second step in this includes dilution of ethanol in the suspension of aqueous gel microcapsules which is later centrifuged to separate them from that of supernatant. The obtained microcapsules then washed by using ethanol and water and again redispersed inside the water. This method allows the preparation of colloidosomes microcapsules having various diameter from several tens to several hundreds of micrometers while in this gel core is utilized to support the particle shell. The particle shell provides the microcapsules sufficient stiffness to get separated from the oil phase by application of centrifugation.

Nanoparticle colloidosomes
These are prepared by using water in oil in water double emulsion as template which formed a robust and monodisperse semi-permeable nanoparticles colloidosomes having tuned structure along with composition. Monodisperse water in oil in water double emulsions having core/shell geometry is produced with the help of glass capillary micro fluidic devices. The hydrophobic silica nanoparticles dispersed inside the water in oil emulsion act as a continuous phase. These particles get self assembled at the interface between the two immiscible liquid phases and which later form a colloidal shell/oil shell to get stabilize the droplets, thus become the colloidosome shells upon removal of the oil solvent. Then they transferred inside the aqueous phase via centrifugation or repeated washings to generate efficient colloidosomes with particles having several microns sizes. The sizes along with dimensions of colloidosomes are controlled by applying control over the flow rates of each fluid phase.

Layer by layer colloidosomes
This method is applied to encapsulate enzymes by utilizing biocrystals as templates for the deposition of polymer multilayers along with enzyme solubilization and release. In this method the there is a formation of hollow polymer capsules while the polyelectrolytes layers get deposited stepwise onto the crystals via use of the surface charge reversal which occurs upon adsorption of each layer. Each polyelectrolyte layer deposited having an opposite charge to that of already adsorbed while the unabsorbed polyelectrolytes is removed using repeated centrifugation or wash redispersion cycles before the next layer is going get deposited. The enzyme solubilization inside the polymer capsules is achieved by exposing the solutions to pH>6 or acidic solution pH<4 which results in a morphology change of the polymer capsule. The release of the enzyme is done by rupturing the polymer capsules which achieved through exposing the solution of pH>11. When the encapsulated enzyme get exposed to oxidizing solution then it results in decomposition of the enzyme which later get expelled from the interior via polymer walls. This leaves the hollow polymer capsule behind which originally used for encapsulation of enzyme.

Non-spherical colloidosomes
For generation of nonspherical colloidosomes having multiple compartments is achieved by using glass capillary Microfluidics to prepare w/o/w double emulsions with several variant morphologies. These double emulsions having a different number of internal aqueous drops inside the oil drop and in this hydrophobic SiO₂nanoparticles get suspended in the oil phase while the poly vinyl alcohol is dissolved inside the continuous aqueous phase, thus it stabilize the double emulsions. By removal of oil the nanoparticles inside the oil phase get converted into shell of colloidosomes while during oil removal the internal w/o interfaces retains their spherical shapes whereas there is deformation of outer o/w interface. This process then leads to the formation of nonspherical colloidosomes having several multiple compartments.

FACTORS AFFECTING COLLOIDOSOMES FORMATION
There are number of factors that might be expected to affect the formation of stable colloidosomes.

Particle size
In this system there is presence of mixture of small and large spherical colloidal particles having opposite electrical charges while small particles get attracted to the surface of large particle due to electrostatic attraction. The bridging flocculation is induced in the case when there is insufficient concentration of smaller particles is present which later get saturated on the surface of one larger particle. The flocculation is induced when the concentration of small particles get exceeded to some critical volume that may produced a sufficient high depletion of attraction between the colloidosomes.

Critical saturation concentration
By application of simple geometric consideration one can calculate the volume fraction of small mono disperses and in compressible particles needed to saturate the surface of a single layer of particles. ^15-17

Critical depletion concentration
The surface of the large molecules when get completely saturated by small particles then any addition of smaller particles additionally inside the system will remain free in the continuous phase hence they will induce a depletion attraction between the large particles. The larger particles get flocculated when the depletion attraction is stronger enough so that it overcome any type of repulsion attraction. The smaller particles which are added inside the system get adsorbed to the surface of the larger particles while the overall concentration of small particles needed for promotion of depletion of flocculation.

Critical adsorption concentration
It largely influences the stability of colloidosomes against aggregation during formation. It is considered as the time taken during the formation for the surface of the large particles to get saturated with the help of smaller particles relative to the time, thus 90% surface get saturated by spherical particles which called as adsorption time while the mechanism involve in the collisions of particles include the Brownian motion. The less aggregation is induced when adsorption time is faster than collision time between the particles.

Effect of surfactants
The high yield of colloidosomes is induced by applying efficient surfactants while it added to oil phase before to introducing the colloidal suspension produces excellent drive of the particles to the edge of the water droplets. The useful application of colloidosomes is limited by the surfactants while for stabilization of water-oil droplets the non ionic surfactant is added.

Effect of sintering time
The stability of colloidosomes is greatly influenced by sintering time and enhancing the sintering time the stability of shell get enhanced which further results in the higher yield of colloidosomes.

Effect of electrolyte
The particle aggregations at the water-oil interface can be achieved by addition of electrolyte in particle stabilized emulsion and resulting can remain stable.

Effect of volume fraction of water
There is alteration in the shape along with stability of colloidosomes is induced by enhancement in the volume fraction of water. ¹⁸

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APPLICATION OF COLLOIDOSOMES
The colloidosomes utilized as encapsulating agent in several fields like biomedical, pharmaceutical along with cosmetic industries. The special application of encapsulation efficiency of colloidosomes is utilized in the drug delivery, cosmetic delivery, food delivery, LCD display devices, polymer blends, paints, catalytic material or living cells. The functional biopolymer acts as a targeting agent while the biopolymers are utilized to direct the colloidosomes to a desired location. Accordingly the resulting colloidosomes can induce an integrated mechanism for targeted delivery of the colloidosomes also potentiates controlled release of the encapsulated material along with biocompatibility with the subjects. The colloidosomes are generated inside the expanded gel state and via entraining the drug in the particle core along with particle expansion which release the drug upon cooling. By altering pH such type of effects is achieved. From this overall study of application of colloidosomes it shows that they can be of immense potential in applications where there is requirement of targeted pulsed-release of active materials. The colloidosomes can be utilized in following several therapeutic along with pharmaceutical application.
1.      Colloidosomes use as drug or protein delivery carrier and which induce the controlled along with sustained drug release.
2.      The colloidosomes apply for enhancement of drug solubilization along with that it also apply for altered pharmacokinetic and biodistribution.
3.      The colloidosomes use widely in several deliveries like ocular drug delivery, brain delivery, DNA delivery along with tumour therapy and antifungal, antiviral, antimicrobial therapy.
4.      The colloidosomes are also utilized for enzyme immobilization.^19-22

CONCLUSION
The colloidosomes are hollow elastic shells having higher in which here is precise control on the permeability along with release is present. The colloidosomes have wide range of application consisting of several fields like humans, ex-beverages, food, pharmaceuticals, pharmaceuticals, flavors, fragrances, cosmetic industries while on the basis of colloidal particles there is variation inside the flexibility is occurred.

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