How to Control the Size of Liposomes

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Size Control in Liposome Preparation

The membrane structure of liposomes is mainly composed of phospholipids and cholesterol. Phospholipids, as the basis of the liposome membrane structure, form a more stable closed vesicle structure with a bilayer due to their amphiphilic nature, with the hydrophilic head aggregated toward one side and the hydrophobic tail toward the other. Cholesterol plays a stabilizing role in the liposome structure, and when environmental conditions change (e.g., temperature, osmotic pressure, pH, etc.), it can play a role in enhancing the stability of the liposome structure. Liposomes have a very important influence on the subsequent stability and encapsulation rate during the whole preparation process due to the size and distribution of the particle size. Therefore, the particle size control of liposomes is the basis of the liposome preparation process and a very important link. There are many methods for liposome particle size control, and it is relatively easy to reduce the particle size to meet the required requirements, so that a stable, reliable, reproducible and application-specific process can be selected according to the needs of production. Organic phase and aqueous phase hydration after the formation of liposomes often the size and distribution of the particle size does not meet the requirements, often need to control the particle size.

Why is the Size of a Liposome Important?

To control the size of liposomes is because the size of liposomes directly affects their properties and applications.

Methods for Controlling the Size of Liposomes

There are many common methods of particle size control (particle size reduction) available for preparation and production, including ultrasound, shear, homogenization, and extrusion.

Ultrasound Technology

Ultrasound is characterized by its concentrated output energy and high density, which is suitable for particle size control of small sized (generally recommended below 10mL) liposome samples of various types, especially suitable for particle size control of drug-carrying liposomes in micro-volume. When ultrasonic waves are used for sample size control, the energy received by the sample particles at different distances from the probe varies greatly, resulting in a large difference in the size of the sample particles in different parts of the container. The more samples and the larger the container, the more obvious this difference is, so the method is not suitable for high-volume industrialized production. Generally speaking, this method is more suitable for liposome thesis research or feasibility study experiments at the project stage. Ultrasound is an ideal choice due to its versatility and low cost.

Shear Technology

The principle of shearing is that the sample particles pass through the narrow gap between the stator and rotor to form a very violent turbulence, and the energy transmitted by the mechanical drive structure shears the sample particles with high linear velocity, so that the sample particles can achieve the effect of refinement. Shearing equipment is very important in the preparation of fat emulsion, but it has been used relatively little in the field of liposomes. This is because the structure of liposomes is relatively weak, in the process of reducing the particle size needs to absorb a certain amount of energy, but the energy can not be too large, otherwise it is easy to cause damage to the structure of the lipid membrane. And shear is characterized by too much energy, control is not careful is easy to excessive, resulting in liposome damage. Therefore, shear equipment in the application of liposome particle size control, it is often necessary to shear technology and mixing, stirring technology, and the design of a specific chamber structure, stator-rotor structure and gap size, and in the process of mass transfer, heat transfer and mechanical (particle surface tension and stress) analysis of the research should be more in-depth, and theoretical calculations based on the process, so as to provide practicality. Because of this specificity, shear is often only special requirements of liposome particle size control applications will be more advantageous, such as some of the special passive drug-carrying liposomes, multivesicular liposomes and so on. Shear is also often used as a process technology in conjunction with other equipment, including homogenization, extrusion, etc.

Extrusion Technology

Liposome extrusion technology makes full use of the structure and performance characteristics of the liposome membrane material, under the conditions of slightly higher than the phospholipid phase transition temperature, driven by a certain pressure, so that the liposome particles through the polycarbonate resin filter membrane, through the shear force of the membrane material to reduce the size of the liposome particles and control its distribution. As the pore size of polycarbonate filter membrane is fixed (such as 50nm, 100nm, etc.), it can effectively ensure that the liposome particles after passing through the filter membrane and its particle size is concentrated in the vicinity of the filter membrane pore size, generally within the range of ± 10% fluctuation, so when the process is well chosen, the extrusion technology can be used to control the distribution of liposome particles in a very narrow range of particle sizes. The process of extrusion can control the particle size distribution of liposome in very narrow range. At present, liposome extrusion technology has been successfully applied to particle size control in the production of adriamycin liposomes, and the effect is much better than other products and technologies in the same period. The selection of liposome extrusion process involves three very important factors, including extrusion temperature, extrusion pressure and extrusion filter membrane.

Since liposome is a synthetic plasma membrane structure similar to cell membrane, its main components are phospholipids and cholesterol. Phospholipids have a certain phase transition temperature, when the liposome temperature in the phase transition temperature of phospholipids, the fluidity of the plasma membrane is better, the performance is flexible, and at this time, through the PC filter membrane more moderate shear can effectively reduce the liposome particle size, and its distribution is controlled within a good range.

Extrusion pressure is the shear force that liposomes are subjected to when they cross the membrane. The size of this shear force directly determines the effect of liposome particle size control. Liposome particles are more flexible and prone to deformation when crossing the membrane, so the filtration speed is particularly important. How to choose a suitable extrusion pressure is very important. The general principle is to increase the pressure as much as possible without damaging the structure of liposome particles, so that the extrusion speed is fast and the effect is good.

Generally speaking, when choosing the pore size of liposome extrusion filter membrane, the original particle size of the liposome sample before extrusion needs to be measured and considered in combination with the final target particle size to be achieved, and then determine what kind of filter membrane to choose. For the extrusion of a particular liposome sample, either a gradient extrusion of a single membrane or the stacking of multiple membranes can be used, and the optimal solution can be selected according to the actual process requirements.

Homogenization Technology

Homogenization technology was first introduced at the 1900 World's Fair in Paris, more than a hundred years ago. Homogenization was originally designed for emulsification of foodstuffs and for controlling the particle size of dairy products. The versatility of homogenization and its unique suitability for scale-up led to its emergence in the pharmaceutical industry. Homogenization technology has been widely used in the liposome industry. Early marketed liposome varieties, such as Amphotericin B and Adriamycin, have adopted homogenization technology as the core equipment for production.

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