Volume 2, Issue 1

February 2015                                                                       By Dr Jane Beh (PrinSus, UNSW Australia)

Controlled Release Nano-Carriers Marching towards Process Intensification

NC Running Man

Why Nano-Carriers?

Targeted drug delivery has been popular in pharmaceutical research for decades. Its great benefits include drug dosage control, drug release rate, improvement of therapeutic efficacy and minimisation of side effects of drugs. Nano-carriers such as liposomes, polymersomes and micelles find useful application in targeted delivery. They carry Active Pharmaceutical Ingredients (APIs) in the human body. As the carriers have long circulation times in the body, they are able to reach the targeted sites because their outer membrane is similar to human body cells.

What are Nano-Carriers?

Liposomes and polymersomes are self-assembled bilayer membrane vesicles containing an aqueous media as the inner core. They are made of amphiphilic molecules, as illustrated in Fig 1. Once they are in contact with water, amphiphilic molecules self-assemble into a bilayer membrane (Fig 2) and eventually into a vesicle (Fig 3). They are able to carry hydrophilic compounds in the aqueous domain, and hydrophobic compounds within the hydrophobic membrane, as illustrated in Fig 3. By comparison, micelles are self-assembled into single layer membranes with hydrophobic domain as the inner core. Hence, micelles can only carry hydrophobic compounds, as shown in Fig 4.

molecules

Why Dense Gas Technology?

The UNSW Australia Process Intensification and Sustainability research group (PrinSus) has been investigating the formation of nano-carriers using dense gas technology for a decade ago. Several conventional methods for production of nano-carriers have limitations such as time consuming, complex procedures, harsh operating conditions and use of large amounts of toxic organic solvents. Additional procedure to thoroughly remove residual organic solvent is essential because organic solvents present occupational and environmental risks, and are non-ideal for pharmaceutical applications. Furthermore, conventional methods have poor control over formation of nano-carriers and their morphologies. Therefore, dense gas technology became an alternative nano-carrier production technique as it is a non-toxic, non-flammable, environmentally acceptable, and economical method.

A novel dense gas technique known as depressurization of an expanded solution into aqueous media (DESAM) was developed to produce liposomes in one-step at moderate temperatures and pressures [2]. The DESAM process uses a dense gas to pre-expand an organic solution that contains the raw materials, which is subsequently introduced into an aqueous media at atmospheric condition by the pressure gradient via a nozzle. The DESAM process was then further investigated to produce other nano-carriers – polymersomes and micelles, and drug encapsulated vesicles (liposomes and polymersomes) [3, 4]. Both residual solvent removal and encapsulation studies by the DESAM process were proven better than the conventional production methods [2, 5-10]. A schematic diagram is illustrated in Fig 5. More details about the DESAM process can be found at: http://www.scopus.com/record/display.url?eid=2-s2.0-84920404437&origin=inward&txGid=19EDE4C0185C055413A20FBD245C3442.N5T5nM1aaTEF8rE6yKCR3A%3a1

Fig 5

A novel continuous dense gas process, known as nano-carrier by a continuous dense gas (NADEG) process has been developed by Beh et al. as an evolution of the batch DESAM process [11]. The main advantage of using a continuous process over a batch process is the increase in production rate while lowering labour demand. Further, the NADEG process was introduced because it has better control over the formation of nano-carriers and reduction of residual solvent levels than the DESAM process. In the NADEG process, a low volume mixing tee (LVMT), as illustrated in Fig 6, was used to achieve better mixing during the formation of nano-carriers when the raw material solutions and an aqueous solution come in contact, in comparison to the DESAM process. The resulting suspension is then delivered to a packed bed from the top of the vessel with supercritical carbon dioxide being introduced from the bottom of the vessel to achieve an efficient organic solvent extraction. A schematic of the NADEG process is shown in Fig 7.

Fig 6 7

Beh et al. has demonstrated that the NADEG process is effectively a 4 times scale up of the batch DESAM process, which is a leap forward to process intensification. In addition, the NADEG process has the ability to reduce the residual solvent in the products to below detectable levels [11]. More details about the NADEG process can be found at: http://dx.doi.org/10.1016/j.cej.2014.12.072

The differences between the DESAM and NADEG processes are summarised in table below:

Table

Reference

[1] C.C. Beh, R. Mammucari, N.R. Foster, Lipids-based drug carrier systems by dense gas technology: A review, Chemical Engineering Journal, 188 (2012) 1-14.
[2] L.A. Meure, The development of a novel process for the formation of liposomes: Depressurisation of an Expanded Solution into Aqueous Media (DESAM), in: Chemical Sciences and Engineering, The University of New South Wales: Sydney, 2004.
[3] C.C. Beh, Formation of nano-carrier systems by dense gas processing, in: School of Chemical Engineering, UNSW Australia, Sydney, Australia, 2013, pp. 225.
[4] C.C. Beh, R. Mammucari, N.R. Foster, Formation of Nanocarrier Systems by Dense Gas Processing, Langmuir, 30 (2014) 11046-11054.
[5] R. Pandey, S. Sharma, G.K. Khuller, Liposome-based antitubercular drug therapy in a guinea pig model of tuberculosis, International Journal of Antimicrobial Agents, 23 (2004) 414-415.
[6] J. Lasch, V. Weissig, M. Brandl, Preparation of liposomes, in: V.W. Torchilin, V. (Ed.) Liposomes: A practical approach, Oxford University Press, 2003, pp. 3-29.
[7] R.C.C. New, Preparation of liposomes, in Liposomes: A Practical Approach, 1990.
[8] D.W. Deamer, Preparation and properties of ether injection liposomes, Annals of the New York Academy of Sciences, VOL. 308 (1978) 250-258.
[9] D. Deamer, A.D. Bangham, Large volume liposomes by an ether vaporization method, Biochimica et Biophysica Acta (BBA) – Biomembranes, 443 (1976) 629-634.
[10] F. Szoka Jr, D. Papahadjopoulos, Procedure for preparation of liposomes with large internal aqueous space and high capture by reverse-phase evaporation, Proceedings of the National Academy of Sciences of the United States of America, 75 (1978) 4194-4198.
[11] C.C. Beh, R. Mammucari, N.R. Foster, Process intensification: Nano-carrier formation by a continuous dense gas process, Chemical Engineering Journal, 266 (2015) 320-328.

 

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