CUBOSOMES- A NOVEL DRUG DELIVERY SYSTEM AND ITS ...

www.wjpps.com Vol 6, Issue 03, 2017.

286

Kala et al. World Journal of Pharmacy and Pharmaceutical Sciences

CUBOSOMES- A NOVEL DRUG DELIVERY SYSTEM AND ITS

FUNCTIONALISATION

Dr. Kala D.* and Aiswarya C.S.

Associate Professor College of Pharmaceutical Sciences, Govt Medical College,

Thiruvananthapuram.

ABSTRACT

Cubosomes are thermodynamically stable self-assembled

nanostructured particle. Their ability to incorporate hydrophilic,

hydrophobic and amphiphilic drugs happens to be their biggest

advantage. They have high payloads due to high internal surface area

and cubic crystalline structure. Targeted and controlled release of

bioactive agents is possible. While most liquid crystalline systems

transform into micelles at higher levels of dilution, cubosomes remain

stable almost at any dilution level because of the relative insolubility of

cubic phase forming lipid in water. So, cubosomes can easily be

incorporated into product formulations. The cubic phases of

cubosomes can be fractured and dispersed to form particulate

dispersions that are colloidally and/or thermodynamically stable for longer time. Cubosomes

have biocompatibile and bioadhesive properties. They are excellent solubilizers, compared

with conventional lipid or non-lipid carriers. The cuboidal system enhances the

bioavailability range twenty to more than one hundred times of water-soluble peptides. They

show enhanced permeation of drug through skin for percutaneous and dermal delivery.

KEYWORDS: Cubosome, stable, biocompatibility, formulation, bioavailability.

INTRODUCTION

Lipids, surfactants and polymer molecules having both polar and non-polar components are

called amphiphilic. The hydrophobic effect drives amphiphiles in polar solvents to

spontaneously self-assemble into a state of thermodynamically stable liquid crystalline phase.

Cubosomes are nanostructured particles of bicontinuous cubic liquid crystalline phase. Cubic

liquid crystals are physically transparent and isotropic phases that are stable in excess water

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 6.647

Volume 6, Issue 03, 286-300 Review Article ISSN 2278 – 4357

*Corresponding Author

Dr. Kala D.

Associate Professor

College of Pharmaceutical

Sciences, Govt Medical

College,

Thiruvananthapuram.

Article Received on

26 Dec. 2016,

Revised on 26 Jan. 2017,

Accepted on 06 Feb. 2017

DOI: 10.20959/wjpps20173-8673


287


and show a unique system for the production of pharmaceutical dosage forms. The liquid

crystals of cubic phase are used in the controlled release of selected water and oil soluble

molecules. They are isotropic, viscous and solid like liquid crystalline substances with cubic

crystallographic symmetry.[1]

Liquid crystal is a state of matter that has properties between

those of conventional liquids and solid crystals. Cubic phases have a thermodynamically

stable structure consisting of two separate, continuous but non intersecting hydrophilic

regions divided by a lipid bilayer. This allows the incorporation of water and oil soluble

materials and also amphiphiles into the system. Lipid based cubic system is biocompatible,

and bio adhesive. Bicontinuous nature of such cubic phases differentiates them from micellar

or discontinuous cubic system containing micelles packed in cubic symmetry.[2]

STRUCTURE OF CUBOSOMES

When cubic phase is dispersed into small particles, these particles are termed cubosomes. The

internal and structural changes of cubosomes could be controlled by adjustment in lipid

composition.

Cubosomes are discrete, sub- micron nanostructures having the same

microstructure as the parent cubic phase.[3]

Their size ranges from 10-500 nm in diameter.

They appear like dots square shaped or slightly spherical.

Figure 1: Square or Spherical shaped Cubosomes

Each dot corresponds to the presence of pore containing aqueous phase cubic phases in lipid-

water system. These were first identified using x- ray scattering technique by Luzzati and

Husson. Monoglycerides are polar lipids with poor water solubility that exhibit aqueous

phase behavior reflecting their structural similarity to non-ionic surfactants. Bulk cubic phase

is formed by hydration of monoolein at levels between 20-40% w/w. Cubic phases are found

sandwiched between lamellar and hexagonal liquid crystalline phases. The ability to exist in


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several different phases is an important property of pure lipids and lipid mixtures; it depends

on temperature, hydration and lipid class. In general monoglycerides exhibit different phase

behaviors when they exposed to water.[4]

Cubosomes are single crystal structures with visible unilamellar vesicles and dispersed

lamellar liquid crystalline phase particles. Increasing the polymer to monoolein ratios leads to

formation of larger vesicles. Ultrasonication of bulk cubic phases produces vesicles which in

due course of time transforms into cubosomes via membrane fusion. Such meta stability is

characteristic of cubosome systems. This is due to slow transport processes involved in

forming high viscous crystalline structures. Also high energy is required to fragment these

bulk cubic phases.

Figure 2: Cubosomes exhibiting its cavernous internal and cubic structure and its

membrane composition with different drug loading modalities

DIFFERENCE BETWEEN CUBOSOMES AND LIPOSOMES[5]

Though there are many similarities between cubosomes and liposomes regarding the mode of

loading and drug delivery, there are pronounced differences too. Some of the major

differences are summarized below:

SL NO: CUBOSOMES LIPOSOMES

1.

Cubosomes are formations of

bicontinuous cubic liquid crystalline

phase by hydrating mixture of

monoolein and poloxamer 407.

Liposomes are formations of vesicles by

hydrating mixture of cholesterol and

phospholipids.

2. Appear like dots square shaped, slightly

spherical of 10-500nm in diameter.

They are artificial, colloidal and spherical

vesicles of 0.05-5.0 μm diameter.

3. In cubosomes active chemical

constituent molecules are anchored

In liposomes, the active principle is

dissolved in the medium of the cavity or in


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through chemical bonds to the polar head

of the phospholipids.

the layers of the membrane. No chemical

bonds are formed.

4.

In cubosomes, polymer and the

individual drug compound form a1:1 or

2:1 complex depending on the substance.

In liposomes, hundreds and thousands of

phosphatidylcholine molecules surround the

water soluble molecule.

MANUFACTURE OF CUBOSOMES[6,7,8]

Presently, cubosomes are prepared mainly by two methods:

1. Top down technique

2. Bottom up technique

1. Top down technique

It is the most widely used method in research area. It was reported in 1996 by Ljusberg-

Wahren. Here the bulk cubic phase is first produced. Then by application of high energy such

as high pressure homogenization, it is processed into cubosome nanoparticles. Bulk cubic

phase resembles a clear rigid gel formed by water-swollen cross-linked polymer chains.

Rupture of the cubic phase occurs as the bilayer breaks under applied shear stresses and flows

along slip planes. They rupture in a direction parallel to the shear direction; the energy

required is proportional to the number of tubular network branches that rupture. The cubic

phase exhibits yield stress that increases with increasing amount of bilayer forming surfactant

and oils. Based on most recent studies, comparison of dispersion produced by sonication and

high pressure homogenization suggests the formation of complex dispersions containing

vesicles and cubosomes with time dependent ratios of each particle type.

Figure 3: Preparation of Cubosomes by Top down approach


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2. Bottom up technique

The bottom-up approach first forms the nanostructure building blocks and then assembles

them into the final material. In this method cubosomes are allowed to form or crystallize from

precursors. The cubosomes are formed by dispersing inverse micellar phase droplets in water

at 80°C and are allowed to slowly cool. Gradually these droplets crystallize to cubosomes.

This is more useful in large scale production of cubosomes. The cubosomes at room

temperature is produced by diluting monoolein-ethanol solution with aqueous poloxamer 407

solution. The cubosomes are spontaneously formed by emulsification. Another process is also

developed to produce the cubosomes from powdered precursors by spray drying technique.

Spray dried powders comprising monoolein coated with starch or dextran form cubosomes on

simple hydration.

Figure 4: Preparation of Cubosomes by Bottom up approach

The bottom-up approach first forms the nanostructure building blocks and then assembles

them into the final material. It is more recently developed technique of cubosome formation,

allowing cubosomes to form and crystallize from precursors on the molecular length scale.

The key factor of this technique is hydrotrope that can dissolve water insoluble lipids into

liquid precursors. This is a dilution based approach that produces cubosomes with less energy

input when compared top down approach.

FUNCTIONALISATION OF CUBOSOMES[9,10]

The concept of functionalization is to control the loading and release properties of the active

ingredient by changing the properties of the cubic phase. Functionalization is achieved by


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incorporating amphiphilic molecules into the liquid crystal. The hydrophobic portion of the

amphiphile inserts into the bilayers of the cubic phase and the hydrophilic portions extend

into the water channels. By customizing the specific properties of the hydrophilic portions, it

is possible to control their interactions with the active ingredient. The release properties at

long times are also altered as the increased affinity between drug and cubic phase alters the

partitioning. Taken together, customizing the properties of the cubic phase is an alternative

method to changing the loading and release properties of a drug offering a greater potential

for tailored release properties over a broader range of applications and conditions.

Figure 5: Drug loading of Cubosomes

One approach to functionalization requires formulating small amphiphiles, such as

surfactants, into the cubic phase. Surfactants used in this method are often termed ‘anchors’.

There must be an optimal set of anchor properties that maximize functionalization without

significantly altering the underlying structure of the cubic phase. Ideal anchors have low

water solubility, low Krafft Temperature, an accessible hydrophilic group with which the

drug can interact, and critical packing parameter (ratio of head group volume and tail

volume) close to unity. Such surfactants typically form vesicles in aqueous solutions. Most

importantly, several reports suggest that the inclusion of anchors alters the loading and

release properties of active ingredients solubilized in the cubic phase. The anchors are added

to greater than 20% w/w without altering the bicontinuous structure of the cubic phase. A

second approach to functionalization is to formulate large amphiphilic polymers or ‘tethers’

into the liquid crystal. In short, functionalization of cubic phases to control and optimize their

loading, release and partitioning of active ingredients is viable across many formulations.


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Given the relative cost of surfactant and pharmaceutical active ingredients, functionalization

seems quite feasible. It also offers greater opportunity for triggered release of drugs as a

result of stimuli such as change in pH, salt levels, or addition of solvent. All these tools are at

the discretion of the formulator.

CUBOSOMES FOR DRUG DELIVERY

Self-assembled cubosomes are attracting increasing interest as active drug delivery systems

as well as biocompatible carriers of large biomolecules including proteins, peptides, DNA

and drugs. Cubosomes have the following advantages for drug delivery:

i) Their ability to incorporate both hydrophilic, hydrophobic, and amphiphilic drug

molecules.

ii) Their characteristics as sustained-release delivery.

iii) Their biocompatibility and bioadhesivity properties.

They have been reported as a burst release delivery system where drug is released by

diffusion from the cubic phase matrix, and that pressure ultrafiltration may have benefits over

dialysis methods for measurement of drug release from colloidal particle-based drug delivery

systems. Research of cubosomes as a drug delivery system has involved oral, intravenous and

percutaneous routes of administration.

1. Transdermal preparations[11]

In the case of skin, the ultimate biological interface is constituted by a thin (~20 micron thick)

cross linked biopolymer called the stratum corneum. It is the chief obstacle to successful

passage of a molecule or drug into the living epidermis and the bloodstream. A

nanostructured cubic phase can be juxtaposed with the stratum corneum for therapeutic or

drug delivery purposes. Thus an interface between the cubic phase and the underlying stratum

corneum, and by extension, between the stratum corneum and the underlying epidermis can

be developed. Before formulating a suitable dosage form, the biocompatibility of monoolein

preparations or other conceivable cubic phases needs to be established.

There are certain conclusions derived after many experiments

a) Bulk cubic phases are difficult to handle and difficult to apply to human skin. In contrast,

the relatively anhydrous lamellar phase of the monoolein-water admixture is relatively

fluid and easy to apply.


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b) The addition of exogenous water to the lamellar phase of a topically applied monoolein-

water admixture results in formation of the more viscous cubic architecture. Thus, the

simple addition or removal of exogenous water provides a means of controlling the phase

behavior and, thus, the physical nature of the topical gel.

c) There is no effect of film thickness to decrease the water vapor gradient. High viscosity

and high vapor permeability are two physical properties distinguishing monoolein-water

cubic phases from occlusive skin ointments such as petrolatum.

d) The cubic phase is hygroscopic on human skin. Thus, exogenous water is sequestered in

the cubic gel architecture and may result in a phase change.

2. Oral drug delivery[12]

Cubosomes can be used to overcome the varied challenges in oral delivery of numerous

compounds including poor aqueous solubility, poor absorption and large molecular size.

These are both liquid and powder in capsule products comprising of self-emulsifying liquid

crystalline nanoparticles technology (LCNP). In an alternative application, large proteins

have been encapsulated for local activity in the gastrointestinal tract. In sustained release,

particles are designed to form in situ in a controlled rate, which enables an effective in vivo

distribution of the drug. Liquid crystalline nanoparticles can also be released at different

absorption sites, which is important for the drugs that have narrow regional absorption

window.

3. Intravenous drug delivery[12]

Lipid nanoparticles comprising of interior liquid crystal structures are used to solubilize,

encapsulate and deliver medications to disease areas within the body. While emulsions and

liposomes have found use as intravenous carriers in drug products, cubosomes increased

payloads of peptides, proteins and many insoluble small molecules and are ideal carriers for

injection or infusion of many actives.[18]

4. Controlled release drug delivery[13]

Control release of solubilized substance is the most popular application of cubosomes. Cubic

phase is more applicable for controlled release because of its small pore size (5-10nm),

ability to solubilize hydrophilic, hydrophobic, amphiphilic molecules and its biodegradability

by simple enzymes. Liquid crystalline nanoparticles technology carriers can also be released

at different absorption sites, for example in the upper or lower intestine.


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5. Other drug delivery methods

a) Cubosomes were found a promising low-irritant vehicle for the effective ocular drug

delivery of flurbiprofen.

b) In-vitro studies showed cubosomes as promising lipid carriers for transcutaneous

immunization.

c) Cubosome particles produced by fragmenting a cubic crystalline phase of monoolein and

water in the presence of stabilizer Poloxamer 407 improved its preocular retention and

ocular bioavailability.

d) Odorranalectin-modified cubosomes offers a novel effective and noninvasive system for

brain drug delivery, especially for peptides and proteins.

e) The development of cationic lipid functionalized nonlamellar nanostructured

nanoparticles may lead to improved short interfering ribonucleic acid delivery vehicles.

f) Monoolein-based cubosomes doped with two fluorescent probes (fluorescein and dansyl)

were successfully exploited for single living cell imaging.

CUBOSOMES IN CANCER THERAPY[14,15]

Passive targeting exploits the pathophysiological properties of the tumour vasculature which

is generally highly disorganized with enlarged gap junctions between endothelial cells and

compromised lymphatic drainage allowing for the extravasation of nanocarriers with sizes up

to several hundred nanometers. Passive targeting is largely dependent on the ability of a drug

nanocarrier to exhibit an increased circulation lifetime resulting in enhanced accumulation at

the target site. Circulation time is dictated by the nanoparticle physicochemical properties

(size, charge, biodegradability, solubility, shape, rigidity), which can be easily manipulated.

The most common modification used to evade macrophage capture and increase circulation

time is accomplished by making the nanoparticle surface hydrophilic through the addition of

a polyethylene glycol coating on the surface. As a means of increasing recognition of target

cells by nanoparticles, active targeting has been implemented.

Active targeting utilizes specific ligands such as peptides or antibodies that bind to molecules

specifically expressed or overexpressed on target cells. Thus, active targeting does not

actually improve overall accumulation at the tumour site, but rather enhances cellular uptake

of the particles following their passive extravasation due to the leaky vasculature. Transferrin

and folate ligands are two examples of commonly used active targeting moieties in

nanomedicine formulations targeting tumours.


295


Despite the ample evidence and extensive research effort supporting the benefits of both

passively and actively targeted nanomedicines in the treatment of cancer, clinically, both

strategies have met with only moderate success. This is because the complexity of the tumor

microenvironment (tumor heterogeneity, vascularity, location) is commonly overlooked and

the extravasation, accumulation and penetration of nanomolecules into the tumors

compromised. Half of the tumor volume tumor is occupied by noncancerous cells and dense

extracellular matrix. Also, the hyper permeable nature of the tumor vasculature allows fluid

to leak from the vessel into the tumor microenvironment, thereby causing extraordinarily

high interstitial pressure throughout the tumor interior. Finally, malignant cells within solid

tumors tend to be tightly packed and are heterogeneous in nature.

Figure 6: Action of Cubosome incorporated drug on tumors

Dacarbazine a water soluble drug, is currently used as a first line chemotherapy medication

against melanoma. It is potent, but has some side effects. Firstly, it is normally administered

intravenously, which is painful. Secondly, the absorption of dacarbazine is generally erratic,

slow and incomplete. Thirdly, the drug is light sensitive and unstable. These limitations can

be overcome by encapsulating this drug using nanocarriers intended for controlled drug

delivery. Because of the three-dimensional nanostructure with hydrophobic and hydrophilic

domains, cubosomes have been considered as a potential candidate for the loading of this

drug.


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EVALUATION OF CUBOSOMES

The cuboidal dispersions can be evaluated by following parameters:

• Thermal analysis[16]

It is used to evaluate the physical status of the drug within the cubosomes. Ingredients of the

cubosomes seem to melt together in temperature of around 37oC to 56

oC which may results in

plasticizing of glycerylmonooleate. The thermal events related to the drug’s melting point are

different from those of the native drug (no sharp drug melting peak at around 200oC). The

thermal events observed between200°C and 300°C may be related to glycerylmonooleate

degradation process.

• Polarized light microscopy[17]

Polarized light microscopy can be used to reveal the optically birefringent (possibly

vesicular) surface coating of the cubosomes and also can distinguish between anisotropic and

isotropic substances. Samples were viewed between crossed polarizers and a λ-sheet in a

Zeiss III light microscope.

• Cryo-transmission electron microscopy[18]

A small amount of prepared sample at ambient conditions is placed on a pure thin bar 600-

mesh TEM grid. The solution was blotted with filter paper to form a thin film spanning the

hexagonal holes of the TEM grid. The sample is then vitrified by immersing into liquid

ethane near its freezing point. This is transferred to a transmission electron microscope for

imaging using a cryoholder with temperature maintained at 175°C. Images are recorded

digitally by a charge coupled device camera using an image processing system.

• X-ray diffraction measurements (XRD)[19]

This method can be used to identify the spatial arrangements of different groups in the

sample. The XRD is carried out using a Philips PW 1830X-ray generator. Samples were held

in vacuum tight cylindrical cell provided with Mylar windows. Diffraction data are collected

at 25°C controlling the temperature. The diffraction patterns obtained are converted to plots

of intensity versus q value, which enable the identification of peak positions, and their

conversion to Miller Indices. The Miller Indices could then be correlated with known values

for different liquid crystalline structures and space groups to identify the dominant internal

nanostructure of the sample.


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• Drug content of dispersions[20]

The drug content of dispersions is evaluated by diluting the filtered dispersion sample in

methanol (1:9 v/v) and analyzed for drug content by high performance liquid chromatography

with the respective procedure. For sedimentation field flow fractionation and stability studies,

the amount of drug detected by HPLC after filtration was taken as reference of the total

amount of drug.

• Tape stripping[21]

In this parameter the 200 mg of each hydrogel formulations is applied on defined cutaneous

sites of forearm (three sites of application for each formulation induplicate). Spread the

preparations uniformly by solid glass rod at the site and are then kept for 6h. After this

period, the residual formulations are removed by wiping with cotton balls. Twenty individual

2 cm squares of adhesive tape are utilized on the application sites. Weigh each tape removed

with stratum corneum cells then determination of stratum corneum removed by difference of

weights; quantify the drug content in the tapes by some analytical technique.

• Photon correlation spectroscopy[22]

Particle size distributions of cubosomes are mainly determined by dynamic laser light

scattering using Zeta sizer (Photon correlation spectroscopy). The sample diluted with a

suitable solvent is adjusted to light scattering intensity of about 300 Hz and measured at 25°C

in triplicate. The data can be collected and generally shown by using average volume weight

size. The zeta potential and polydispersity index can also be recorded.

• Pressure Ultrafiltration Method[23]

Drug release measurement of cubosomes can be done by pressure ultrafiltration method. It is

based closely on that proposed by Magenheim et al using an Amicon pressure ultrafiltration

cell fitted with a Millipore membrane at ambient temperature (22±2)°C.

APPLICATIONS OF CUBOSOMES

● Cubosomes are widely used in melanoma therapy.

Cosmetic companies like L’Oreal and Nivea are trying for the use of cubosome particles

as oil-in-water emulsion stabilizers and pollutant absorbents in cosmetics.

More recent patent activities points to the use of cubosomes in personal care product

areas as varied as skin care, hair care, cosmetics and antiperspirants.


298


They have been shown to provide a vehicle for several in vivo delivery routes, including

depot, transdermal, mucoadhesion and ophthalmic.

Due to the microbicidal properties of monoglycerides, cubosomes could be used to design

intravaginal treatment of sexually transmitted diseases caused by viruses or by bacteria.

The cubosome technology is used to develop a synthetic vernix– the cheesy white

substance that coats infants in late gestation – to help premature infants who are born

without it.

Control release of solubilized substance is the most popular application of cubosomes.

Commercial applications of cubosomes have been developed for periodontal disease that

is based on triglyceride–monoolein mixtures combined with the drug metronidazole.

Cubosome carriers can be used to release drugs at different absorption sites, for example

in the upper or lower intestine, which is important for the drugs that have narrow regional

absorption window.

It forms a thin surface film at mucosal surfaces consisting of a liquid crystal matrix whose

nanostructure can be controlled for achieving an optimal delivery profile and provides

good temporary protection of sore and sensitive skin.

CONCLUSION

The use of nanomedicine in localized drug delivery has received a lot of attention over the

past couple of decades and resulted in several clinically approved formulations. These

systems have been shown to have a number of advantages over conventional

chemotherapeutics; however, they have not yet reached their full potential as anticancer

agents. With the sequence of human genome, biotechnology companies are developing a

peptide and protein based drugs. It is expected that in the next 10 to 20 years, cubosomes

containing protein and peptide based drugs will constitute more than half of the new drugs

introduced into the market and more than 80% of these protein drugs will be antibodies due

to control release activity. Further specialized studies are required to confirm this fascinating

hypothesis and to better investigate the role of vesicles and cubosomes in controlling the

release of the drug.

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