INTRODUCTION:

In the bicontinuous cubic liquid crystalline phase, cubosomes are discrete, sub-micron-sized nanostructured particles. Larsson came up with the moniker "cubosomes," which refers to the structure's cubic molecular crystallography and resembles liposomes. These nanoparticles are liquid crystalline surfactant particles that have self-assembled in the right amount of water with the right kind of microstructure. Amphiphilic compounds include lipids, surfactants, and polymer molecules that contain both polar and non-polar components. Molecules that contain active chemical constituents are coordinated by chemical A drug delivery system is a tool and formulation that securely transports a therapeutic agent to a particular bodily location at a predetermined rate to achieve an effective concentration at the site of drug action. Controlled release (CR) is the word for the drug's pre-planned release to support therapeutic advantages from reducing harmful side effects.

These systems are made up of loaded, stable liquid crystalline aggregates that transport the active components. The incorporation of pharmaceuticals into intricate internal domain structures that enable diffusion-controlled drug release into the surrounding external aqueous environment binds to the polar head of the phospholipids in cubosomes. Depending on the material, a 1:1 or 2:1 complex ratio is formed between the polymer and the specific medicinal component. When the cubic phase breaks, colloidally and thermodynamically stable particle dispersions can result. Cubosomes are bicontinuous cubic liquid crystalline phases formed by hydrating a monoolein and poloxamer 407 mixture, and they play a significant role in nanodrug formulations.¹

Structure of Cubosomes:

The two internal aqueous channels of cubosomes were separated by honeycombed structures, and there was also a significant amount of interfacial space. Cubosomes are a type of nanoparticle, or more precisely, a type of nanostructure, that are created by the self-assembly of molecules that are similar to amphiphilic or surfactant molecules and have cubic crystallographic symmetry. The cubosomes have cubic crystalline structures and a large interior surface area. Due to their interesting bicontinuous structures, which contain two distinct areas of water and divide them by continuous water and oil channels, the cubic phases have a very high solid-like viscosity, which is a special feature. where "bicontinuous" describes a bilayer-separated pair of different hydrophilic areas. The structure's interconnectivity produces a transparent, viscous gel with a rheology and look like cross-linked polymer hydrogels. Yet, cubic gels based on monoglycerides have great biocompatibility and substantially more long-range order than hydrogels.^2-3

Figure 1: Structure of cubosomes separating two internal aqueous channels along with large interfacial area

Advantages⁴:

1. They can encapsulate pharmaceuticals that are both hydrophilic and hydrophobic as well as amphiphilic.

2. They possess properties of sustained-release medication delivery.

3. Cubosomes contain qualities that make them biocompatible and bioadhesive.

4. Cubosomes' bicontinuous cubic liquid crystalline phase is even stable in excess water.

5. Compared to typical lipid or non-lipid carriers, cubosomes are good solubilizers. are applied to the care of body tissues such as the skin, hair, and others.

6. They have a high drug carrier capacity for a variety of medicines that are only weakly water-soluble.

7. They are a great way to shield the delicate medicine from enzymatic and in-vivo breakdown caused by peptides and proteins.

8. Water-soluble peptides have a bioavailability range of twenty to more than one hundred times higher thanks to the cuboidal structure.

9. Compared to liposomes, cubosomes have a higher breaking resistance and a bigger ratio between the bilayer area and particle volume.

10. They have significant pharmacological payloads due to their large interior surface area and crystalline cubic architectures.

11. They have lipid biodegradability and can be made using an easy process.

12. Controlled and targeted release of bioactive substances.

13. Compared to typical lipid or non-lipid carriers, cubosomes are good solubilizers.

14. They are a great way to prevent peptides and proteins, as well as enzymatic and in-vivo degradation, from destroying the sensitive medicine.

15. They are cost-effective and non-toxic.

Disadvantage⁴

1. Due to cubosomes' high viscosity, large-scale manufacture might occasionally be challenging.

2. Due to the high concentration of water inside cubosomes, there is a low entrapment of medications that are water-soluble.

3. When made of drug forms based on polymers, cubosomes do not provide regulated drug distribution.

4. Cubosomes may have a low drug loading efficiency and may cause drug leakage during production, preservation, and transport in vivo; as a result, its main flaw of stability functions as a roadblock and restricts their utilization.

5. Since they contain a lot of water inside their structure, medication molecules.

Applications⁴

1. Localized Drug Action

2. Transdermal Drug Delivery

3. Intravenous Drug Administration Systems

4. In The Treatment Of Viral Infections

5. Melanoma Therapy

6. Treatment Of Skin, Hair and Body Tissue

7. Sustained Drug Release Behaviour

Method of Preparation of Cubasome^5-6

Monoglycerides exhibit different phase behaviours when they exposed to water. Surfactants, which are used in the production of cubosomes, are poloxamer 407 in a concentration range between 0% and 20% w/w with respect to the disperse phase. The concentration of the monoglyceride/surfactant mixture generally takes between 2.5% and 10% w/w with respect to the total weight of the dispersion. Polyvinyl alcohol used in alternative to poloxamer as stabilizing agent in the dispersion. There are four techniques for preparation of cubosomes which are;

1) TOP-DOWN TECHNIQUE:

It is the most extensively used approach, and LjusbergWahren first mentioned it in 1996. Cubosomes nanoparticles are produced by first manufacturing bulk cubic phase and then processing it with high energy methods such high pressure homogenization. Bulk cubic phases resemble a clear, stiff gel made of crosslinked polymer chains that have been expanded by water. The cubic phases are distinct because they have a periodic liquid crystalline structure and are one thermodynamic phase. When cubic phases break, they do so in a direction that is parallel to the direction of shear; the energy needed is equal to the number of broken branches in the tubular network. The bulk cubic phase is first manufactured and then separated into nanoparticles called cubosomes using high energy processing. This method is the one that is most widely utilised in research. While cubic phases resemble liquid crystalline forms, bulk cubic phases approximate a transparent, stiff gel created by water-swollen cross-linked polymer chains. The cubic phases show that the yield stress rises as the number of bilayer-forming oils and surfactants increases. Dispersed liquid crystalline particles are produced at transitional shear rates, where overcome free bulk phase reforms at higher shear rates. According to Warr and Chen, cubic phases may act as lamellar phases during dispersion with increasing shear. According to the majority of known studies, complex dispersions containing vesicles and cubosomes with varying ratios of each particle can form similarly to the dispersion created by sonication and high-pressure homogenization. The D-surface structure of coarse cubosomes at the micron scale is identical to that of the developing bulk cubic phase. however, due to the additional polymers following homogenization, the P-surface takes the lead.

2) BOTTOM-UP TECHNIQUE:

Precursors are permitted to crystallise or develop into cubosomes. Cubosomes are created by scattering L2 or inverse micellar phase droplets in water at 80°C, allowing the droplets to cool slowly, and then allowing the droplets to crystallise. When cubosomes are produced on a vast scale, this is more active. By combining aqueous poloxamer 407 solutions with monoolein ethanol solution, cubosomes can be created at room temperature. By emulsifying, the cubosomes are automatically created. Another approach is being explored to create cubosomes using spray drying from powdered precursors. On simple hydration, spray-dried powders like monoolein coated in starch or dextran create cubosomes. The polymers provide cubosomes colloidal stability on their own. Cubosomes are allowed to develop or crystallise from their predecessors in this process. The bottom-up method initially creates the basic components of the nanostructure before assembling them into the finished product. It is a more contemporary way of cubosomes production that enables cubosomes to form and crystallise from molecular-scale progenitors. The hydrotrope, which can turn water-insoluble lipids into liquid precursors, is the fundamental component of this process. When opposed to a top-down approach, this dilution-based method uses less energy to generate cubosomes.

3) SONICATION METHOD:

Monoolein was gently melted in water bath at 70ºC which was then injected dropwise into preheated poloxamer 407(P407) solution at 70ºC, maintained under mechanical stirring at 1500rpm for 5min. Dispersions were cooled to room temperature and then sonicated at maximum power of for 1min After equilibration for 24hours, cubosomes dispersions were obtained.

4) SPRAY DRYING METHOD:

The precursors for powdered cubosomes were obtained using this technique. Dextran and monoolein were initially dissolved in water and ethanol, respectively, to produce the quaternary system (each forms an optically isotropic solution). After that, the lipid phase was added to the dextran solution and the two solutions were combined and stirred for 15 minutes. The quaternary system produced an emulsion after being combined. To encourage ethanol and water evaporation, the emulsion was spray dried using a Labultima LU-222 spray dryer at a rate of 6ml/min at an exit temperature of 140^oC. Spray drying produced a polymer-coated powder precursor that, when hydrated, would result in cubosomes dispersion. Glyceryl monooleate (GMO) and poloxamer 407 will be ultrasonically processed to create cubosomes in aqueous media. Briefly, triamcinolone will be added to the melting solution of GMO and poloxamer 407 at 60°C to create a transparent, uniform liquid. The lipid solution is maintained at a mechanical stirrer at 1500rpm for 10minutes, and water is then added drop by drop. The resulting dispersion is then further sonicated in a probe sonicator for 20minutes at 120W. After 24hours of equilibration, cubasomal dispersion will form.

Procedure for Preparation of Cubosomes^7-8

The Cubasomal Formulation was Prepared Using Glyceryl Mono Oleate And Polaxamer 407. Twelve Different Batches Were Prepared By Varying Glyceryl Mono Oleate From 2.5 To 5% And GMO Was Gently Melted In Water Bath At 70^oC.Which Then Injected Drop Wise Into Preheated Poloxamer 407solution At 70c And Drug 5Mg Was Added And Made Up to 20ml By Gradually Adding Distill Water.This Solution Was Maintained Under Mechanical Stirring At 500rpm For 5 Min Dispersion Were Cooled To Room Temperature And Then Sonicated At Maximum Power of 120W For 5Min. After Equilibrium For 24 Hrs Cubasome Milky White Dispersion Were Obtained.

Evaluation of Cubosomes:^9-10

Visual inspection:

The cubosomes are visually assessed for optical appearance (e.g colour, turbidity, homogeneity, presence of macroscopic particles).

Shape of the cubosomes:

Transmission electron microscopy can be used to view the shape of the cubosomes.

Particle size distribution:

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.

Zeta potential:

The magnitude of zeta potential indicates the degree of electronic repulsion between adjust, similarly charge particle. Zeta potential is key indicator of the stability of formulation.

Entrapment efficiency:

The entrapment efficiency of cubosomes can be determined using ultra filtration techniques. In the later technique, unentrapped drug concentration is determined, which is subtracted from the total drug added. The amount of drug is analyzed by using spectrophotometer.

Measurement of drug release^11-2

Drug release from cubosomes can be done by pressure ultrafiltration method. It is based on that proposed by Magenheim et al. using an Amicon pressure ultrafiltration cell fitted with a Millipore membrane at ambient temperature (22±2)°C. 5.7. Stability studies the physical stability can be studied by investigation of organoleptic and morphological aspects as a function of time. Particle size distribution and drug content can be assessed at different time intervals can also be used to evaluate the possible variations by time.

Future prospects:^13-15

Before such nanocarriers can truly realise their therapeutic potential in treating many diseases, further optimization is still needed, depending on the route of administration, frequency of dosing, and mode of drug release. Cubosomes nanoparticles show promise in the field of drug delivery and sustained drug release. They are also appealing nano vehicles for loading and delivering proteins and peptides, but the reported studies are still at an early stage Moreover, little is known about the biological mechanisms that influence cubosomes drug release, structural changes brought on by contact with biological fluids including plasma, interactions with cell membranes, and infusion-related reactions, to name a few. Although the use of cubosomes for intravenous drug delivery is ambitious, these nanocarriers may find quicker uses for the oral, ophthalmic, and topical delivery of medications with low water solubility, providing a different but more practical potential in formulation science. and various issues regarding the structural and morphological characteristics of these soft nanocarriers, the ability to load bio macromolecules, and the release of those loaded macromolecules should be addressed. The early stages of formulation development for cubosomes-based intravenous nanomedicines should address blood compatibility.

CONCLUSION:^16-17

Cubosomes are nanoparticles, but they are self-assembled liquid crystalline particles rather than solid particles. They can contain a variety of hydrophilic and lipophilic medicines and exhibit sustained and targeted drug delivery. Producing cubosomes using either high pressure homogenization or top down and bottom-up procedures, such as ultrasonication, is a simple process. Cubosomes are useful for a variety of immunological compounds, proteins, therapeutic prospects, and cosmetics. The cubasomal formulations may be widely used as targeted drug delivery systems for ophthalmic, diabetic, and anticancer therapy due to the possible site specificity. The cubosomes technology is relatively new, has a high output, and offers a lot of potential for research into creating novel formulations that are also viable from a business and industrial standpoint.

Table 1: Recent Formulated Cubosome^18-23

API	Treatment	Polymers	Year
Miconazole Nitrate	Treatment of Superficial Candidiasis, Dermatophysis And Pityriasis Versicolor	Glyceryl Monoloeate (GMO) and Poloxamer 407	2014
Capsaicin	To Treat Pain-Related Disorders	Glyceryl Monoloeate (GMO) and Poloxamer 407	2015
Clotrimazole	As Skin Retentive System	Glyceryl Monoloeate (GMO) and Poloxamer 407	2019
Dexamethasone	To Treat Various Inflammatory	Glyceryl Monoloeate (GMO) and Poloxamer 407	2020
Ketoprofen	To Treat Various Inflammatory	Glyceryl Monoloeate (GMO) and Poloxamer 407	2020
Curcumin	Treatment of Osteomyelitis	Glyceryl Monooleate and Pluronic F-127	2023

REFERENCES:

1. Rizwan SB, Dong YD, Boyd BJ, Rades T and Hook S. Characterisation of bicontinuous cubic liquid crystalline systems of phytantriol and water using cryo field emission scanning electron microscopy. Micron. 2007: 38; 478–85. doi: 10.1016/j.micron.2006.08.003.

2. Karami Z. Cubosomes: Remarkable drug delivery potential. Drug Discovery Today. 2016; 21: 789–801. doi: 10.1016/j.drudis.2016.01.004

3. Venkateswara R. A Review on Cubosome: The Novel Drug Delivery System, GSC Biological and Pharmaceutical Sciences. 2018; 5(1): 076–081. doi.org/10.30574/gscbps.2018.5.1.0089

4. Barauskas J. Cubic phase nanoparticles (cubosomes): Principles for controlling size, structure, and stability. Langmuir. 2005; 21; 2569–77. doi: 10.1021/la047590p

5. Garg G. Cubosomes: An Overview, Biol. Pharm. Bull., 2007; 30: 350–3. doi: 10.1248/bpb.30.350

6. Murgia S. Drug loaded fluorescent cubosomes: Versatile nanoparticles for potential theragnostic applications. Langmuir. 2013; 19: 6673–9. https://doi.org/10.1021/la401047a

7. Borne J. Effect of lipase on monoolein-based cubic phase dispersion (cubosomes) and vesicles. J. Phys. Chem. B. 2002, 106. https://doi.org/10.1021/jp021023y

8. Esposito E., et al. Cubosome dispersions as delivery systems for percutaneous administration of indomethacin. Pharm. Res. 2005; 22: 2163–73. doi: 0.1007/s11095-005-8176-2

9. Kojarunchitt T., Development and characterisation of modified poloxamer 407 thermoresponsive depot systems containing cubosomes. Int. J. Pharm. 2011; 408. doi: 10.1016/j.ijpharm.2011.01.037

10. Bei D. Formulation of dacarbazine-loaded cubosomes-part I: influence of formulation variables., 2009; 1032–39. doi: 10.1208/s12249-009-9293-3

11. Deepak P and Dharmesh S. Cubosomes: A Sustained Drug Delivery Carrier. Asian J. Res. Pharm. Sci. 2011; 1(3): 59-62. Doi: 10.52711/2231-5659

12. Kanchan R. Pagar, Sarika V. Khandbahale. A Review on Novel Drug Delivery System: A Recent Trend. Asian Journal of Pharmacy and Technology. 2019; 9(2): 135-140. DOI: 10.5958/2231–5713

13. Kanti Sahu, Rishita Pathak, Naveen Agrawal, Pinkesh Banjare, Harish Sharma, Gyanesh Sahu. A Review of the Novel Drug Delivery System used in the Treatment of Cancer. Research Journal of Pharmaceutical Dosage Forms and Technology. 2019; 11(3): 199-205. DOI: 10.5958/0975-4377

14. Pandey Swarnima, Kumar Sushant. Nanoparticulate Drug Delivery Systems: An update. Research Journal of Pharmaceutical Dosage Forms and Technology. 2021; 13(4): 312-316. DOI: 10.5958/0975-4377

15. Kalyankar T., Butle S., Chamwad G. Application of Nanotechnology in Cancer Treatment. Research J. Pharm. and Tech. 2012; 5(9): 1161-1167. DOI: 10.5958/0974-360X

16. G.O. Birajdar, V.S. Kadam, A.G. Chintale, P.D. Halle, M.K. Nabde and K.S. Maske. A Comprehensive Review on Nanotechnology. Research J. Pharm. and Tech. 2013; 6(5): 486-494. DOI: 10.5958/0974-360X

17. Dr. D.K. Sanghi, Rakesh Tiwle. Herbal Drugs an Emerging Tool for Novel Drug Delivery Systems. Research J. Pharm. and Tech. 2013; 6(9): 962.-967. DOI: 10.5958/0974-360X

18. Samia M. Formulation and Evaluation of Cubosomes as Skin Retentive System for Topical Delivery of Clotrimazole. Journal of Advance Pharmacy Research. 2019; 3(2): 68-82. DOI:10.21608/APRH.2019.9839.1079

19. Vishal N. Development, Characterization and Evaluation of Cubosomes Loaded Smart Gel for the Treatment of Osteomyelitis using 32 Factorial Design. Ind. J. Pharm. Edu. Res. 2023; 57(3): 695-702.

20. Venkatesh B. Formulation And Evaluation Of Miconazole Nitrate As A Cubosomal Topical Gel. Journal of Global Trends in Pharmaceutical Sciences. 2014; 5(4): 2037-2047.

21. Thoutreddy R. Formulation and Evaluation of Dexamethasone Loaded Cubosomes. Research J. Pharm. and Tech. 2020; 13(2): 709-714. Doi: 10.5958/0974-360X.2020.00135.3

22. Anand B. Formulation and Evaluation of Cubosomal Gel of an Anti-Inflammatory Agent. Pharm Sci. 2020; 10: 103. doi: 10.31531/2231-5896.1000103.

23. Xinsheng P. Characterization of cubosomes as a targeted and sustained transdermal delivery system for capsaicin. Drug Design, Development and Therapy. 2015; 9: 4209–4218.

Received on 06.06.2023 Modified on 17.01.2024

Research J. Pharm. and Tech. 2024; 17(8):4063-4067.

DOI: 10.52711/0974-360X.2024.00630