INTRODUCTION:

Among the liquid crystalline structures self-assembled from aqueous surfactant systems, bicontinuous cubic phases possess a special status. Bicontinuous cubic phase liquid crystals are newly discovered exotic materials originally found in the most unexpected places. The original observations of cubic liquid crystalline phase came during the study of polar lipids, such as monoolein (Fig. 1), that are used as food emulsifiers^{1, 2}. Bicontinuous cubic liquid crystalline materials are an active research topic³ because their unique structure lends itself well to controlled release applications. Cubosomes are discrete, sub-micron, nanostructured particles of bicontinuous cubic liquid crystalline phase⁴. These nanostructured particles⁵, of a liquid crystalline phase with cubic crystallographic symmetry are liquid instead of solid. Cubosomes are typically produced by high-energy dispersion of bulk cubic phase, followed by colloidal stabilization using polymeric surfactants. After formation of the cubosomes, the dispersion is formulated into a product and then applied to a substrate of interest, usually bodily tissue⁶.

Fig. 1: Structure of monoolein

Cubosomes offer a large surface area, low viscosity and can exist at almost any dilution level. They have high heat stability and are capable of carrying hydrophilic and hydrophobic molecules⁷. Combined with the low cost of the raw materials and the potential for controlled release through functionalization, they are an attractive choice for cosmetic applications as well as for drug delivery. However, at present cubosomes do not offer controlled release on their own⁸. They have also been modified using proteins^{9, 10}. Bulk cubic phase is formed by hydration of monoolein at levels between 20-40% w/w. Cubic phase is unique and desirable as a result of its mesoscale structure: a contorted lipid bilayer separating two continuous but non-intersecting water regions^{11, 12}. The tortuous structure of bulk cubic phase provides controlled release of solubilized active ingredients¹³, while cubosomes exhibit burst release because of their sub-micron length scales¹⁴. Cubosomes have been patented for use as active delivery vehicles¹⁵, emulsion stabilizers¹⁶, and pollutant scavengers^{17, 18} in various pharmaceutical and personal care products^{19, 20, 21, 22}.

PRODUCTION OF CUBOSOMES:

Two main approaches are used to produce cubosome particles. The top-down approach applies high energy to fragment bulk cubic phase^23-25. The bottom-up approach forms cubosomes from molecular solution by, for example, dilution of an ethanol-monoolein solution²⁶. Top-down or high-energy techniques require formation of cubosomes prior to their use in a product. Bottom-up techniques avoid high-energy drawbacks and allow formation of cubosomes in use by a consumer or during product formulation. Both techniques require a colloidal stabilizer, like the tri-block copolymer Poloxamer 407, to prevent cubosome aggregation²⁷.

Fig. 2: Regular cubic lattices of cubosome

Cubosome formation by any method, even dispersion of bulk cubic phase, requires some time for the viscous cubic phase to crystallize from less-ordered precursors²⁸. Well-formed cubosomes with regular cubic lattices are visible in Fig. 2, as are less ordered cubosomes and simple vesicles, indicating the kinetic dependency of cubosome formation. The mechanism of cubosome formation by high energy dispersion is clearly the fragmentation of bulk cubic phase into smaller pieces. The dilution process produces sub-micron cubosomes in the absence of fluid shear by dilution of an isotropic liquid precursor, but the exact cubosome formation mechanism is not known²⁶.

PRECURSOR FORMS OF CUBOSOME:

Liquid Cubosome Precursors:

Following the difficulty and expense of high-shear dispersion of viscous bulk cubic phase to form cubosomes, it is desirable to seek less aggressive processes of manufacture. High-energy processes being expensive and difficult to scale-up, also proves to be harmful to thermosensitive ingredients like proteins. In some product applications, the in situ formation of cubosomes is desired, such as during hand washing or mouth rinsing. To avoid high-energy processing and produce them in situ a strong driving force exists resulting in the development of a liquid phase precursor to cubosomes. The hydrotrope dilution process is found to consistently produce smaller, more stable cubosomes. In this process the particles are formed by nucleation and growth, as employed in crystallization and precipitation processes. This is achieved by dissolving the monoolein in a hydrotrope (ethanol) which prevents liquid crystalline formation. All this is achieved without the need of high shear, minimizing the risk of degrading the cubic liquid crystalline structure²⁹.

The liquid precursor process allows for easier scale up of cubosome preparations and avoids bulk solids handling and potentially damaging high energy processes.

Powdered Cubosome Precursors:

Powders composed of dehydrated surfactant coated with polymer are termed as powdered cubosome precursors. Hydration of the precursor powders forms cubosomes with a mean particle size of 600 nm, as confirmed by light scattering and cryo-TEM^{30, 31}. A water-soluble non-cohesive starch coating on the waxy lipid prevents agglomeration and allows control of particle size. The lipids used to make cubosomes are waxy, sticky solids, rendering them unable to form small discrete particles. Spray drying technique is an excellent process to produce these particles. Spray drying produces encapsulated particles from an emulsion of liquid droplets or a dispersion of solid particles in a concentrated aqueous polymer solution. Nozzle is used for the continuous and dispersed phases spraying throughout to create suspension droplets that are contacted with a heated, dry air stream flowing in the opposite direction. As a result of this excess water immediately evaporates, leaving dry powder particles composed of the dispersed phase encapsulated by a shell of the formerly dissolved polymer. Spray-drying processes are easily scaled up and are already widely employed for manufacturing consumer products like detergents and foods. Moreover, the process provides an easy route to preload active drug into the cubosomes prior to drying. Finally, the polymer coating on the powder imparts surface properties to the hydrated cubosomes that can be tailored by proper selection of the encapsulating polymer. Such powders offer some process and performance advantages to liquid phase hydrotropic cubosome precursors.

CUBOSOME APPLICATIONS:

Drug delivery vehicle is a common application for such new materials. The rapid expansion of the life-sciences industry is expected to drive previously “exotic” delivery vehicles and ingredients into broader marketplaces, such as personal care and consumer products³². Landh and Larsson³³ describe the cubosome usage in numerous medical and controlled release applications. Boyd⁸ specifies that controlled release is usually possible only for bulk cubic phases. Consequently, self-assembled surfactant phases have been extensively examined for compatibility with numerous medical active ingredients and their applications³⁴.

The number of research in association with 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^{35, 36, 37, 38, 39, 40}. Moreover, these researches have also discovered that a second amphiphile, phytantriol (Fig. 3), has an aqueous phase behavior sufficiently close to that of monoolein to form cubosomes under similar conditions.

Table 1: List of drugs incorporated in cubosome for sustained drug delivery

Researcher	Drug	Category	Associated Disease
Engstrom et al.⁵¹	2-amino-1-phenylpropanol HCl	Antidepressant	Mania, depression
	Nitroglycerin	Anti-anginal	Angina pectoris
	Oestriol	Hormonal therapy	Atrophic vaginitis, pruritus
Sadhale et al.⁵²	Cefazolin	Antibiotics	Genito-urinary, respiratory tract infection
	Cefuroxime	Antibiotics	Meningitis, bone and soft tissue infection
	Prilocaine	Local anesthetic	In Dentistry
Damani⁵³	Clindamycin phosphate	Antibiotics	Peritonitis, staphylococcal bone andjoint infection
Engstrom et al.⁵⁴	Clomethiazole	Psychotropic	Insomnia
Engstrom et al.⁵⁵	Clotrimazole	Antifungal	vagina, mouth, and skin infection
Engstrom et al.⁵⁶	Gramicidin	Topical steroid	Corticosteroid sensitive dermatoses
Engstrom et al.⁵⁶	Insulin	Hypo/Hyper glycaemics	Diabetes mellitus
Nielsen et al.⁵⁷	Indomethacin	NSAIDs	Gout, rheumatoid arthritis
	Isosorbide mononitrate	Anti-anginal	Angina pectoris
	Lidocaine hydrochloride	Aural prepration	Fungal infection of external ear
Boyd⁸	Diazepam	Sedative-hypnotic	Anxiety, insomnia, seizures
	Rifampicin	Bactericidal antibiotic	Tuberculosis
	Griseofulvin	Antifungal	Fungal infection of skin
	Propofol	Hypnotic	Procedural sedation, to induce and maintain Gernal Anesthesia

Fig. 3: Structure of phytantriol

Even more recent patent activity by points to cubosome use in personal care product areas as varied as skin care, hair care, cosmetics, and antiperspirants^41,42,43,44. Despite recent activity, there remains a lack of the practical elements like manufacturing scalability and material customization that is necessary to lead formulators to consider using cubosomes in commercial products. The cubic phase has been shown to provide a vehicle for several in vivo delivery routes, including depot⁴⁵, transdermal⁴⁶, mucoadhesion⁴⁷ and ophthalmic⁴⁸. Because of fusogenic property of monoolein it increases the penetration of macro molecules⁴⁹.

A wide variety of drugs with different physicochemical properties have been incorporated in cubosomes, and their sustained release behavior was also studied Table 1. Sustained behavior of cubosomes was because of cubosome remnant particles⁵⁰. Monoglyceride based cubosome dispersion can be proposed for topical use, such as for perctuneous or mucosal applications. Because of the microbicidal properties of monoglycerieds, could be used to design intravaginal treatment of sexually transmitted diseases caused by viruses (e.g. HSV, HIV) or by bacteria (e.g. Chlamydia trachomatis and Neisseria genorrticae. Due to similarity between the cubic phase structure and the structure of the stratum corneum, it is reasonable to suppose the formation of mixture of cubosomal monolein with stratum corneum lipids. This kind of interaction might lead to the formation of a cubosome depot in this layer, from which drug can be released in a controlled fashion. The cubosome technology is used to develop a synthetic vernix– the chessy white substance that coats infants in late gestation – to help premature infants who are born without it. The vernix is a complex mixture of lipid (fats), proteins and water. It is formed late in gestation and has an integral role in normal skin development^{58, 59}.

CONCLUSION:

Cubic phase materials can be formed by simple combination of biologically compatible lipids and water and are thus well suited for pharmaceutical and body tissue. The ability to form cubosomes either in use, during formulation, or during manufacture offers greatly enhanced flexibility for product development efforts. The precursor forms enhance its further scope in technological field. Moreover, the literature reviews also specifics cubosomal utility as a controlled release drug carrier.

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Received on 19.07.2011 Accepted on 08.08.2011

Asian J. Res. Pharm. Sci. 1(3): July-Sept. 2011; Page 59-62