By Maja Hunter, Ph.D.

Liposomes and lipid nanoparticles are often used as a drug delivery system. Most conventional techniques of liposome formation are complex procedures, which use organic solvents or require harsh process conditions that may lead to denaturation of active ingredients [1]. Strict regulatory requirements and safety rules in the pharmaceutical industry call for complete removal of organic solvents in the final formulations. Unavoidable steps of additional purification and waste disposal lead to increased costs in production [1, 2]. In 2015, Sercombe et al. discussed reasons why liposome-based formulations don´t make it into clinical practice:

1. The clinical trials of liposomal formulations require a number of control groups to account for different aspects of the drug delivery system.

2. The patented intellectual property of liposome-based therapies slows down the developmental process since all the permissions need to be acquired and documentation obtained. This contributes to delays and increases costs.

3. Lastly, they touch upon quality assurance, involving the manufacturing process and stability of the formulation. For potential issues in 2015, the authors stated:

   1. scalability of the manufacturing process

   2. reliability and reproducibility of the final product

   3. lack of equipment and/or in-house expertise

   4. chemical instability or denaturation of the encapsulated compound in the manufacturing process

   5. long-term stability [3].

Since then, research efforts have been focused on developing technologies for solvent-free production of liposomes. One way to prepare liposomes is with the supercritical fluids (SCFs) method, where supercritical CO2 is used. Non-flammable, non-toxic, non-corrosive, inexpensive, environmentally acceptable gas is suitable for use with thermosensitive materials and allows batch or continuous production of liposomes [1].

Solvent-free liposome preparation with high-shear processing method

In 2020, Khadke et al. published a scientific paper, describing scalable solvent-free production of liposomes using a high-shear processor [4]. They modified the production process of two liposome-based products, liposomes loaded with soluble doxorubicin or poorly soluble amphotericin B, so no organic solvents were used in the process. The resulting formulations had characteristics of the original products currently approved for clinical use [4].

Liposomal drug delivery systems were characterized in terms of particle size, polydispersity index, zeta potential and drug loading. The variations in operating pressure and number of passes had an influence on the particle size and polydispersity index but had no effect on drug loading and drug release [4]. This gives the high-shear processor user the freedom to produce liposomes within a given target size range.

The applied high pressure forces the product to pass through the microchannels of the Reaction Chamber® module. High speed and shear forces heat up the product, which is cooled down with a heat-exchanger, just after it exits the Reaction Chamber® module. As the exiting temperature can be tightly controlled, temperature-sensitive samples can be processed as well.

However, liposomes are not the only drug delivery system that can be processed using high-shear processing. Solid lipid nanoparticles (SLNs) can encapsulate both hydrophilic and hydrophobic drugs. SLN dispersions are identical to oil-in-water emulsions, except the liquid lipid is exchanged by a solid lipid at room temperature [5]. Recently, more scientific papers describe solvent-free methods, using high pressure homogenizers for preparation of lipid nanoparticles [5, 6].

Why to choose Dyhydromatics ShearJet® high-shear processors for preparation of liposomes and lipid nanoparticles?

Most of the issues previously mentioned regarding large-scale production of liposomes can be solved using Dyhydromatics ShearJet® high-shear processors.

1. Scalability of the manufacturing process. Due to the Reaction Chamber® technology, the procedures developed in the research lab are linearly scalable to large-scale production.

2. Reliability and reproducibility of the final product. Reaction Chamber® technology ensures constant processing conditions, so every mL of the sample gets the same treatment. The results are consistent and reliable.

3. Controlled cooling of the sample. Shear and impact forces contribute to heating of the sample. The sample temperature is controlled by a heat exchanger to prevent denaturation of the encapsulated compound in the manufacturing process.

4. High quality final product. The processing procedure is reliable and reproducible, which reflects in quality of the final product.

5. Versatility. High-shear processing allows batch and continuous production.

6. GMP-environment friendly. Dyhydromatics ShearJet® processors are able to fulfill strict requirements of the pharmaceutical industry as the procedures are readily recorded and the equipment can be cleaned or steamed in place (CIP/SIP). The product-contact parts are autoclavable.

7. Dyhydromatics team. We like to call ourselves the full package. The experienced Dyhydromatic team (Engineering through Customer Service) is ready to help you with any challenge that comes your way.

Long term stability heavily depends on the composition of the formulation. On the nano level, gravitational forces become negligible and electromagnetic forces dominate. Do nanoparticles in the processed formulation repel or attract each other? If the answer is  repel, then you are on the right track to manufacture a formulation with long term stability.

If you are interested in our equipment, a Proof of Concept testing of your application, or you want to learn more about our technology, do not hesitate to reach out to our friendly customer service. We look forward to answering your questions. Visit our website at www.dyhydromatics.com.

Literature

[1] Leitgeb M, Knez Ž, Primožič M (2020) Sustainable technologies for liposome preparation. J. Supercrit. Fluids. 165. doi: 10.1016/j.supflu.2020.104984

[2] Wagner A, Vorauer-Uhl K. (2011) Liposome technology for industrial purposes. J Drug Deliv. 2011:591325. doi: 10.1155/2011/591325

[3] Sercombe L, Veerati T, Moheimani F, Wu SY, Sood AK and Hua S (2015) Advances and Challenges of Liposome Assisted Drug Delivery. Front. Pharmacol. 6:286. doi: 10.3389/fphar.2015.00286

[4] Khadke S, Roces CB, Donaghey R, Giacobbo V, Su Y, Perrie Y. Scalable solvent-free production of liposomes. J. Pharm. Pharmacol., 2020. 72(10);1328-1340. doi: 10.1111/jphp.13329

[5] Potta SG, Minemi S, Nukala RK, Peinado C, Lamprou DA, Urquhart A, and Douroumis D. Development of Solid Lipid Nanoparticles for Enhanced Solubility of Poorly Soluble Drugs. J. Biomed. Nanotech, 2010. 6(6):634-640. doi: 10.1166/jbn.2010.1169

[6] Amasya G, Aksu B, Badilli U, Onay-Besikci A, Tarimci N. QbD guided early pharmaceutical development study: Production of lipid nanoparticles by high pressure homogenization for skin cancer treatment. Int. J. Pharm, 2019. 563:110-121. doi: 10.1016/j.ijpharm.2019.03.056

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