INTRODUCTION:

Cubosomes are discrete, sub-micron, nanostructured particles of the bi continuous cubic liquid crystalline phase.¹The term Cubosomes was coined by Larsson, which reflects the cubic molecular crystallography and similarity to liposomes.

These are nanoparticles which are self-assembled liquid crystalline particles of certain surfactants with proper ratio of water with microstructure. Cubosomes are nanoparticles but instead of the solid particles usually encountered, these are self-assembled liquid crystalline particles with a solid like rheology that provides unique properties of practical interest².

Most probably cubosomes are composed of polymers, lipids and surfactants with polar and non-polar components hence said as amphiphilic. The amphiphilic molecules are driven by the hydrophobic effect into polar solvent to impulsively identify and assemble into a liquid crystal of nanometerscale³.

Thus, cubosomes are bicontinuous cubic liquid phase enclosing two separate regions of water divided by surfactant-controlled bilayers.

Further these are similar to liquid crystalline substance with cubic crystallographic symmetry and are optically isotropic, viscous and solid too. The cubic phase can fracture and form colloidally and thermodynamically stable particulate dispersions⁴. Cubosomes have great importance in nanodrug formulations and are formations of bicontinuous cubic liquid crystalline phase by hydrating mixture of monoolein and poloxamer. Dots Square shaped, slightly spherical of 10 - 500nm in diameter.

In cubosomes active chemical constituent molecules are anchored through chemical bonds to the polar head of the phospholipids⁵. The polymer and the individual drug compound form a 1:1 or 2:1 complex depending on the substance.

Despite the early recognization (in 1980) large scale manufacture of cubosomes was difficult due to their complex phase behavior and viscous properties⁶. Effort to develop scalable processes to produce cubosomes in large scale is under development. A few anticancer drugs have been successfully encapsulated in cubosomes and characterized⁷.

Advantages:

1. It is economic.

2. It is non-toxic and biocompatible.

3. Method of preparation is simple.

^4.It has excellent bio adhesive properties^8.

5. It has skin permeation enhancement.

6. For longer time they are thermodynamically stable.

^7.Capability of encapsulating hydrophilic, hydrophobic and amphiphilic substances^9.

8. Targeted release and controlled release of bioactive agents.

9. Due to high internal surface area & cubic crystalline structures there is high drug loading.

Disadvantages:

1. Due to presence of large amounts of water inside cubosomes there is low entrapment of water- soluble drugs^10,

2. Because of the high viscosity the large-scale production is sometimes difficult.

3. Large scale production is difficult for sometimes because of high viscosity.

Structure of cubosome:

The basic structure of cubosomes includes honeycombed structures separating the two internal aqueous channels along with large interfacial area¹¹. Cubosomes are nanoparticles, more accurately nanostructure particles of liquid crystalline phases with cubic crystallographic symmetry formed by the self-assembly of amphiphilic or surfactant like molecules. The cubic phases possess a very high solid like viscosity, which is a unique property because of their intriguing bicontinuous structures which enclose two distinct regions of water separated by a controlled bilayer of surfactant application^12,Amphiphilic molecules form bicontinuous water and oil channels, where bicontinuous refers to two distinct (continuous, but non-intersecting) hydrophilic regions separated by the bilayer. The interconnectedness of the structure results in a clear viscous gel similar in appearance and rheology to cross-linked polymer hydrogels.¹³

Fig.1 Structure of Cubosome

Materials Used In Cubosome Formation:

Natural lipids, cationic and non-ionic surfactants, and polymer systems all contain bicontinuous cubic phases¹⁴.The monoglyceride monoolein, which spontaneously forms bicontinuous cubic phases upon the addition of water, is the lipid that is most frequently employed to create these phases. Monoglycerides are also relatively insoluble and temperature-resistant. Monoolein is the primary precursor to cubosomedevelopment¹⁵.

Glycerides of oleic acid and other fatty acids are combined to form monoolein, which primarily contains monooleate. There are two ways to obtain monoolein: as a mixed glyceride form or as distilled monoolein. Due to its high purity, distilled monoolein is favoured for pharmaceutical purposes.

Monoolein naturally appears as a waxy yellow paste with a distinctive odor. It expands when submerged in water, forming a number of lyotropic liquid crystalline formations. Monoolein is a substance that is nontoxic, biodegradable, and biocompatible and is categorized as GRAS (generally regarded as safe)¹⁶.

It is also present in nonparenteral medications that are approved in the UK and the FDA's list of inactive components. Monoolein exhibits the mesomorphic phase, which is crucial for better understanding the lipid's potential for use in pharmaceuticals.

Typically, when exposed to water, monoglycerides display a variety of phase behaviors. Poloxamer 407, one of the surfactants employed in cubosome synthesis, is present in concentrations ranging from 0% to 20% w/w with regard to the disperse phase. Depending on the weight of the entire dispersion, the concentration of the monoglyceride/surfactant mixture typically ranges from 2.5% to 10% w/w. As a stabilizing ingredient for the dispersion, polyvinyl alcohol is employed as an alternative to poloxamer.

Fig. 2 Formation Method of Cubosome.

Method of Prepration:

Cubosomes can be manufactured by two different techniques as shown in figure

· Top Down Technique

· Bottom Up Technique

1. TOP DOWN TECHNIQUE 2. BOTTOM UP TECHNIQUE

Fig.3 Manufacturing techniques of cubosomes

Method of Preparation Formation

· Fabrication Method

· Emulsification Method

1. Fabrication Method:

GMO/p407 cubic gel GMO 5% and P407 1.0% were melted at 60°C in a hot water bath, then the necessary quantity of medication was added, and the mixture was continually stirred until it was dissolved^17. Drop by drop of deionized water is added, and a vortex is activated to homogenize the mixture. The optically isotropic cubic gel formed after 48 hours of storage at room temperature, was agitated by mechanical stirring into a crude dispersion, and then was broken up by a sonicater probe with a 200W energy output while at a cold temperature of 20°C in a water bath for 20min.

2. Emulsification Method:

The GMO and P407 are added to the water in this procedure, and after ultrasonication, the 5% GMO, 1% P407, and 5% ethanol in 89% water are removed¹⁸. At 60°C, GMO and P407 are melted and combined. Ethanolic solution is added to the melting process. The resulting combination is added dropwise to deionized water that has been prepared to 70°C. It is then ultrasonically processed for 50 minutes at the same temperature using a maximum power of 130kW. The dispersion solution is then maintained at room temperature and shielded from light.

Evaluation of cubosome:

1. Visual Inspection of Cubosome:

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

2. Shape of Cubosome:

For viewing the shape of the cubosomes. Transmission electron microscopy can be used.

3. Particle Size Distribution:

The primary method for determining the particle size distributions of cubosomes is dynamic laser light scattering with a Zeta sizer^19.(Photon correlation spectroscopy). An appropriate solvent is used to dilute the sample, which is then tested in triplicate at 25°C with a light scattering intensity set to roughly 300 Hz. Utilizing average volume weight size, the data can be gathered and commonly displayed. Additionally, it is possible to record the polydispersity index and zeta potential.

An appropriate solvent is used to dilute the sample, which is then tested in triplicate at 25°C with a light scattering intensity set to roughly 300 Hz. Utilizing average volume weight size, the data can be gathered and commonly displayed. Additionally, it is possible to record the polydispersity index and zeta potential.

4. Zeta Potential:

The size of the zeta potential represents the strength of the electrical attraction between two similarly charged particles. Zeta potential is a crucial indicator of the formulation's stability.

5. Entrapment Efficiency:

The effectiveness of cubosome trapping can be assessed utilizing ultra filtration techniques²⁰ In the latter method, the concentration of the unentrapped medication is calculated and deducted from the total drug added. A spectrophotometer is used to measure the amount of the medication.

6. Measurement of Drug Release:

Pressure ultrafiltration can be used to liberate drugs from cubosomes. It is based on that suggested by Magenheim et al. employing an Amicon pressure ultrafiltration cell equipped with a Millipore membrane at room temperature (222°C).²¹

7. Stability Studies:

By examining organoleptic and morphological features as a function of time, the physical stability can be investigated. It is also possible to measure the drug content and particle size distribution at various time intervals in order to assess potential temporal fluctuations^22,23.

Application:

1. In Cancer Therapy:

Recently, various anti-cancer medications were successfully encapsulated in cubosomes and their physicochemical features were evaluated²⁴.This intriguing nano carrier's distinctive structure points to melanoma therapy as a possible use for it. Different strategies have been considered to specifically target nanomedicines to tumors, with preclinical and clinical research demonstrating the viability of passive and active cancer cell targeting²⁵.

2. Oral Drug Delivery:

Recently, various anti-cancer medications were successfully encapsulated in cubosomes and their physicochemical features were evaluated. This intriguing nano carrier's distinctive structure points to melanoma therapy as a possible use for it. Different strategies have been considered to specifically target nanomedicines to tumors, with preclinical and clinical research demonstrating the viability of passive and active cancer cell targeting²⁶.

3. Intravenous Drug Delivery System:

Medicines are solubilized, encapsulated, and delivered to illness locations within the body using lipid nanoparticles with internal liquid crystal structures of curved lipid membranes²⁷. The cubosome nanoparticle exhibits higher peptide, protein, and numerous insoluble small molecule payloads as compared to emulsions and liposomes, and these characteristics make them excellent injection carriers.²⁸

4. Topical Drug Delivery System:

Due to their higher bioadhesiveness, cubosomes are ideal for the topical and mucosal administration of many medicines²⁹. The use of liquid crystal and liquid crystal nanoparticle technologies' distinctive features forms the basis of topical delivery methods. In situ forming bioadhesive liquid crystal systems, which are used in topical drug delivery systems, allow for precise and efficient drug administration to mucosal surfaces such as the vagina, ocular, and buccal³⁰.

5. Drug Deliver Vehicles:

Drug delivery vehicle is a common application for such new materials. The 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 cosmetics³¹.

6. Control And Sustain Release Behaviour:

Numerous medications with various physicochemical characteristics have been added to cubosomes, and their sustained drug release behavior has also been investigated³¹.Cubosome residual particles were responsible for the cubosomes' sustained behavior. It is possible to suggest using monoglyceride-based cubosomes topically, such as through mucosal or percutaneous administration^32.

7. In Treatment of Viral Disease:

Because monoglycerieds have microbicidal capabilities, they could be used to create intravaginal treatments for sexually transmitted diseases brought on by bacteria and viruses including Chlamydia trachomatis and Neisseria meningitidis³³.

CONCLUSION:

Cubosomes are nanoparticles but instead of the solid particles, cubosomes are self-assembled liquid crystalline particles, they have ability to incorporate many hydrophilic and lipophilic drugs and shows sustained and targeted drug delivery. Two methods such as top down and bottom-up approaches could be easily employed to produce cubosomes either by ultrasonication techniques or high-pressure homogenization. Cubosomes are applicable to wide range of drug candidates, proteins, immune substances and also to cosmetics. Due to the potential site specificity, the cubosomal preparations may be widely employed as targeted drug delivery systems for ophthalmic, diabetic and also for anticancer therapy. The cubosome technology is relatively new with high output and would have wide scope of research in developing new formulations with commercial and industrial viability compliance with ethical standards.

REFERENCE:

1. Bhosale RR, Osmani RA, Harkare BR, Ghodake PP. Cubosomes: the inimitable nanoparticulate drug carriers. Scholars Academic Journal of Pharmacy. 2013; 2(6):481-6.

2. Chaudhary K, Sharma D. Cubosomes: a potential drug delivery system. Asian journal of pharmaceutical research and development. 2021 Oct 15; 9(5):93-101.

3. Shimizu T, Ding W, Kameta N. Soft-matter nanotubes: a platform for diverse functions and applications. Chemical reviews. 2020 Feb 4; 120(4):2347-407.

4. Chaudhary K, Sharma D. Cubosomes: a potential drug delivery system. Asian journal of pharmaceutical research and development. 2021 Oct 15; 9(5):93-101.

5. Abourehab MA, Ansari MJ, Singh A, Hassan A, Abdelgawad MA, Shrivastav P, Abualsoud BM, Amaral LS, Pramanik S. Cubosomes as an emerging platform for drug delivery: A review of the state of the art. Journal of Materials Chemistry B. 2022; 10(15):2781-819.

6. Gupta T, Kenjale P, Pokharkar V. QbD-based optimization of raloxifene-loaded cubosomal formulation for transdemal delivery: Ex vivo permeability and in vivo pharmacokinetic studies. Drug Delivery and Translational Research. 2022 Dec; 12(12):2979-92.

7. Zaki RM, Alkharashi LA, Sarhan OM, Almurshedi AS, Aldosari BN, Said M. Box Behnken optimization of cubosomes for enhancing the anticancer activity of metformin: Design, characterization, and in-vitro cell proliferation assay on MDA-MB-231 breast and LOVO colon cancer cell lines. International Journal of Pharmaceutics: X. 2023 Dec 15; 6:100208.

8. Chaudhary K, Sharma D. Cubosomes: a potential drug delivery system. Asian journal of pharmaceutical research and development. 2021 Oct 15; 9(5):93-101.

9. Zakaria F, Ashari SE, Azmi ID, Rahman MB. Recent advances in encapsulation of drug delivery (active substance) in cubosomes for skin diseases. Journal of Drug Delivery Science and Technology. 2022 Feb 1; 68:103097.

10. Teba HE, Khalil IA, El Sorogy HM. Novel cubosome based system for ocular delivery of acetazolamide. Drug Delivery. 2021 Jan 1; 28(1):2177-86.

11. Abourehab MA, Ansari MJ, Singh A, Hassan A, Abdelgawad MA, Shrivastav P, Abualsoud BM, Amaral LS, Pramanik S. Cubosomes as an emerging platform for drug delivery: A review of the state of the art. Journal of Materials Chemistry B. 2022; 10(15):2781-819.

12. Jain SK, Kamath K, Vindhya VS, Shabaraya AR. CUBOSOMES IN THE TREATMENT OF HERPES SIMPLEX VIRAL INFECTION. European Journal of Biomedical. 2023; 10(4):53-8.

13. Chaudhary K, Sharma D. Cubosomes: a potential drug delivery system. Asian journal of pharmaceutical research and development. 2021 Oct 15; 9(5):93-101.

14. Chaudhary K, Sharma D. Cubosomes: a potential drug delivery system. Asian journal of pharmaceutical research and development. 2021 Oct 15; 9(5):93-101.

15. Abourehab MA, Ansari MJ, Singh A, Hassan A, Abdelgawad MA, Shrivastav P, Abualsoud BM, Amaral LS, Pramanik S. Cubosomes as an emerging platform for drug delivery: A review of the state of the art. Journal of Materials Chemistry B. 2022; 10(15):2781-819.

16. Rehman A, Tong Q, Jafari SM, Assadpour E, Shehzad Q, Aadil RM, Iqbal MW, Rashed MM, Mushtaq BS, Ashraf W. Carotenoid-loaded nanocarriers: A comprehensive review. Advances in colloid and interface science. 2020 Jan 1; 275:102048.

17. Suresh AM, Kallingal A. Cubosomes Nanoparticles: Recent Advancements in Drug Delivery. Int J Med Phar Sci| Vol. 2020 May; 10(02):11.

18. Nasr M, Teiama M, Ismail A, Ebada A, Saber S. In vitro and in vivo evaluation of cubosomal nanoparticles as an ocular delivery system for fluconazole in treatment of keratomycosis. Drug Delivery and Translational Research. 2020 Dec; 10:1841-52.

19. Bessone CD, Akhlaghi SP, Tártara LI, Quinteros DA, Loh W, Allemandi DA. Latanoprost-loaded phytantriolcubosomes for the treatment of glaucoma. European Journal of Pharmaceutical Sciences. 2021 May 1; 160:105748.

20. Shravani Y, Ahad HA, Haranath C, gari Poojitha B, Rahamathulla S, Rupasree A. Past Decade Work Done on Cubosomes Using Factorial Design: A Fast Track Information for Researchers. (2021). Int. J. Life Sci. Pharma Res.; 11(1): P124-135.

21. Desai TB, Patil SB, Tipugade OB, Malavi SB. Cubosomes: The next generations of drug delivery in nanoparticles form. World Journal of Pharmaceutical Sciences. 2021 Jun 1:222-31.

22. Pal A, Gope A, Sengupta A. Drying of bio-colloidal sessile droplets: Advances, applications, and perspectives. Advances in Colloid and Interface Science. 2023 Mar 9:102870.

23. Zaki RM, Alkharashi LA, Sarhan OM, Almurshedi AS, Aldosari BN, Said M. Box Behnken optimization of cubosomes for enhancing the anticancer activity of metformin: Design, characterization, and in-vitro cell proliferation assay on MDA-MB-231 breast and LOVO colon cancer cell lines. International Journal of Pharmaceutics: X. 2023 Dec 15; 6:100208.

24. Gu W, Meng F, Haag R, Zhong Z. Actively targeted nanomedicines for precision cancer therapy: Concept, construction, challenges and clinical translation. Journal of controlled release. 2021 Jan 10; 329:676-95.

25. Zhai J, Fong C, Tran N, Drummond CJ. Non-lamellar lyotropic liquid crystalline lipid nanoparticles for the next generation of nanomedicine. ACS nano. 2019 May 13; 13(6):6178-206.

26. Kapoor KA, Pandit VI, Nagaich UP. Development and characterization of sustained release methotrexate loaded cubosomes for topical delivery in rheumatoid arthritis. Int J Appl Pharm. 2020; 12(3):33-9.

27. Effiong DE, Uwah TO, Jumbo EU, Akpabio AE. Nanotechnology in cosmetics: basics, current trends and safety concerns—A review. Advances in nanoparticles. 2019 Dec 16; 9(1):1-22.

28. Abourehab MA, Ansari MJ, Singh A, Hassan A, Abdelgawad MA, Shrivastav P, Abualsoud BM, Amaral LS, Pramanik S. Cubosomes as an emerging platform for drug delivery: A review of the state of the art. Journal of Materials Chemistry B. 2022; 10(15):2781-819.

29. Jain K, Ahmad J, editors. Nanotheranostics for Treatment and Diagnosis of Infectious Diseases. Academic Press; 2022 May 21.

30. Garg G, Saraf S, Saraf S. Cubosomes: an overview. Biological and Pharmaceutical Bulletin. 2007; 30(2):350-3.

31. Karami Z, Hamidi M. Cubosomes: remarkable drug delivery potential. Drug discovery today. 2016 May 1; 21(5):789-801.

32. Ha S, La Y, Kim KT. Polymer cubosomes: Infinite cubic mazes and possibilities. Accounts of Chemical Research. 2020 Jan 10; 53(3):620-31.

33. Boge L, Hallstensson K, Ringstad L, Johansson J, Andersson T, Davoudi M, Larsson PT, Mahlapuu M, Håkansson J, Andersson M. Cubosomes for topical delivery of the antimicrobial peptide LL-37. European journal of pharmaceutics and biopharmaceutics. 2019 Jan 1; 134:60-7.

Received on 07.11.2023 Modified on 05.12.2023

Asian J. Pharm. Tech. 2024; 14(1):50-54.

DOI: 10.52711/2231-5713.2024.00010