Ultrasonic Liposome Preparation

Ultrasonically produced liposomes show a very high entrapment efficiency, high loading capacity and uniformly small spherical size. Thereby, ultrasonic liposomes offer excellent bioavailability. Hielscher Ultrasonics offers ultrasonicators for the reliable production of pharma-grade liposomes in batch and continuous mode.

Advantages of Ultrasonic Liposome Production

Ultrasonic liposome encapsulation is a technique used to encapsulate drugs or other therapeutic agents within liposomes using ultrasonic energy. When compared with other methods for liposome encapsulation, ultrasonic encapsulation has several advantages that make it the superior production technique.

  • High loading, high entrapment efficiency: Ultrasonic liposome production is well known to produce liposomes with a high loading of active ingredients, e.g. vitamin C, drug molecules etc. At the same time, the sonication method shows a high entrapment efficiency. This means that a high percentage of the active substance is encapsulated by ultrasonication. In conclusion, this makes ultrasonication a highly efficient method for liposome production.
  • Uniformly small liposomes: One advantage of ultrasonic liposome encapsulation is its ability to produce highly uniform liposomes with a narrow size distribution. Ultrasonic energy can be used to break up larger liposomes or lipid aggregates into smaller, more uniform liposomes. This leads to greater consistency in the size and shape of the liposomes, which can be important for drug delivery applications where the size of the particles can impact their pharmacokinetics and efficacy.
  • Applicable to any molecules: Another advantage of ultrasonic liposome encapsulation is its ability to encapsulate a wide range of drugs and other therapeutic agents. The technique can be used to encapsulate both hydrophilic and hydrophobic drugs, which can be difficult to do with other methods. Additionally, ultrasonic energy can be used to encapsulate macromolecules and nanoparticles, which may be too large to encapsulate with other methods.
  • Quick and reliable: Ultrasonic liposome encapsulation is also a relatively simple and quick process. It does not require the use of harsh chemicals or high temperatures, which can be detrimental to the therapeutic agents being encapsulated.
  • Scale-up: Additionally, the technique can be easily scaled up for large-scale production, making it a cost-effective option for drug delivery applications.

In summary, ultrasonic liposome encapsulation is a superior technique for liposome encapsulation due to its ability to produce uniform liposomes with a narrow size distribution, encapsulate a wide range of therapeutic agents, and its simplicity and scalability.

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Ultrasonication is a fast and reliable technique to produce superior liposomes, nanoliposomes and nano-structured lipid carriers.

UP400St, a 400 watts powerful ultrasonic homogenizer, for the production nano-liposomes.

Ultrasonic Liposome Preparation for Pharmaceuticals and Cosmetics

Liposomes (lipid based vesicles), transferosomes (ultradeformable liposomes), ethosomes (ultradeformable vesicles with high alcohol content), and niosomes (synthetic vesicles) are microscopic vesicles, which can be artificially prepared as globular carriers into which active molecules can be encapsulated. These vesicles with diameters between 25 and 5000 nm are often used as drug carriers in the pharmaceutical and cosmetic industry, such as oral or topical drug delivery, genetherapy, and immunization. Ultrasonication is a scientifically proven method for highly efficient liposome production. Hielscher ultrasonicators produce liposomes with high loadings of active ingredients and superior bioavailability.

Liposomes and Liposomal Formulation

Liposomes are unilamellar, oligolamellar or multilamellar vesicular systems and are composed of the same material as a cell membrane (lipid bilayer). Regarding to their composition and size, liposomes are differentiated as follows:

  • multi-lamellar vesicles (MLV, 0.1-10μm)
  • small unilamellar vesicles (SUV, <100 nm)
  • large unilamellar vesicles (LUV, 100–500 nm)
  • giant unilamellar vesicles (GUV, ≥1 μm)


Ultrasonicator UP200Ht during the preparation of vitamin C liposomes.The main structure of liposomes consists of phospholipids. Phospholipids have a hydrophilic head group and a hydrophobic tail group, which consists of a long hydrocarbon chain.
The liposome membrane has a very similar composition as the skin barrier, so that they can be easily integrated into the human skin. As the liposomes fusionate with the skin, they can unload the entrapped agents directly to the destination, where the actives can fulfill their functions. Thus, the liposomes create an enhancement of skin penetrability/ permeability for the entrapped pharmaceutical and cosmetical agents. Also liposomes without encapsulated agents, the vacant vesicles, are potent actives for the skin, as the phosphatidylcholin incorporates two essentials, which the human organism cannot produce by itself: linoleic acid and choline.
Liposomes are used as biocompatible carriers of drugs, peptides, proteins, plasmic DNA, antisense oligonucleotides or ribozymes, for pharmaceutical, cosmetic, and biochemical purposes. The enormous versatility in particle size and in physical parameters of the lipids affords an attractive potential for constructing tailor-made vehicles for a wide range of applications. (Ulrich 2002)

Ultrasonic Liposomes Formation

Liposomes can be formed by the use of ultrasonics. The basic material for liposome preparation are amphilic molecules derived or based on biological membrane lipids. For the formation of small unilamellar vesicles (SUV), the lipid dispersion is sonicated gently – e.g. with the handheld ultrasonic device UP50H (50W, 30kHz), the VialTweeter or the ultrasonic reactor CupHorn – in an ice bath. The duration of such an ultrasonic treatment lasts approx. 5 – 15 minutes. Another method to produce small unilamellar vesicles is the sonication of the multi-lamellar vesicles liposomes.
Dinu-Pirvu et al. (2010) reports the obtaining of transferosomes by sonicating MLVs at room temperature.
Hielscher Ultrasonics offers various ultrasonic devices, sonotrodes and accessories and can thereby provide the most suitable ultrasonic setup for a highly efficient liposome encapsulation at any scale.

Ultrasonic Encapsulation of Active Substances into Liposomes

Liposomes works as carriers for active ingredients such as vitamins, therapeutic molecules, peptides etc. Ultrasound is an effective tool to prepare and form liposomes for the entrapment of active agents. Simultaneously, sonication assists the encapsulation and entrapment process so that liposomes with a high loading of active ingredients are produced. Before encapsulation, the liposomes tend to form clusters due to the surface charge-charge interaction of phospholipid polar heads (cf. Míckova et al. 2008), furthermore they have to be opened. By way of example, Zhu et al. (2003) describe the encapsulation of biotin powder in liposomes by ultrasonication. As the biotin powder was added into the vesicle suspension solution, the solution has been sonicated. After this treatment, biotin was entrapped in the liposomes.

For the production of liposomes loaded with bioactive molecules, ultrasonic encapsulation is the preferred method.

1kW ultrasonic processor UIP1000hdT for continuous inline production of liposomes

Liposomal Emulsions with Ultrasonication

To enhance the nurturing effect of moisturizing or anti-aging cremes, lotions, gels and other cosmeceutical formulations, emulsifier are added to the liposomal dispersions to stabilize higher amounts of lipids. But investigations had shown that the capability of liposomes is generally limited. With the addition of emulsifiers, this effect will appear earlier and the additional emulsifiers cause a weakening on the barrier affinity of phosphatidylcholine. Nanoparticles – composed of phosphatidylcholine and lipids – are the answer to this problem. These nanoparticles are formed by an oil droplet which is covered by a monolayer of phosphatidylcholine. The use of nanoparticles allows formulations which are capable to absorb more lipids and remain stable, so that additional emulsifiers are not needed.
Ultrasonic emulsification is used to produce skin care products such as creams and lotions with a high load of active substances.Ultrasonication is a proven method for the production of nanoemulsions and nanodispersions. Highly intensive ultrasound supplies the power needed to disperse a liquid phase (dispersed phase) in small droplets in a second phase (continuous phase). In the dispersing zone, imploding cavitation bubbles cause intensive shock waves in the surrounding liquid and result in the formation of liquid jets of high liquid velocity. In order to stabilize the newly formed droplets of the disperse phase against coalescence, emulsifiers (surface active substances, surfactants) and stabilizers are added to the emulsion. As coalescence of the droplets after disruption influences the final droplet size distribution, efficiently stabilizing emulsifiers are used to maintain the final droplet size distribution at a level that is equal to the distribution immediately after the droplet disruption in the ultrasonic dispersing zone.

Liposomal Dispersions using Ultrasonication

Liposomal dispersions, which are based on unsaturated phosphatidylchlorine, lack in stability against oxidation. The stabilization of the dispersion can be achieved by antioxidants, such as by a complex of vitamins C and E.
Ortan et al. (2002) achieved in their study concerning the ultrasonic preparation of Anethum graveolens essential oil in liposomes good results. After sonication, the dimension of liposomes were between 70-150 nm, and for MLV between 230-475 nm; these values were approximately constant also after 2 month, but inceased after 12 month, especially in SUV dispersion (see histograms below). The stability measurement, concerning essential oil loss and size distribution, also showed that liposomal dispersions maintained the content of volatile oil. This suggests that the entrapment of the essential oil in liposomes increased the oil stability.

Long-time stability of ultrasonically prepared multilamellar (MLV) and small unilamellar (SUV) vesicle dispersion.

Ortan et al. (2009): Stability of MLV and SUV dispersions after 1 year. Liposomal formulations were stored at 4±1 ºC.

Hielscher ultrasonic processors are the ideal devices for applications in the cosmetic and pharmaceutical industry. Systems consisting of several ultrasonic processors of up to 16,000 watts each, provide the capacity needed to translate this lab application into an efficient production method to obtain finely dispersed emulsions in continuous flow or in a batch – achieving results comparable to that of todays best high-pressure homogenizers available, such as orifice valves. In addition to this high efficiency in the continuous emulsification, Hielscher ultrasonic devices require very low maintenance and are very easy to operate and to clean. The ultrasound does actually support the cleaning and rinsing. The ultrasonic power is adjustable and can be adapted to particular products and emulsification requirements. Special flow cell reactors meeting the advanced CIP (clean-in-place) and SIP (sterilize-in-place) requirements are available, too.

The table below gives you an indication of the approximate processing capacity of our ultrasonicators:

Batch Volume Flow Rate Recommended Devices
0.5 to 1.5mL n.a. VialTweeter
1 to 500mL 10 to 200mL/min UP100H
10 to 2000mL 20 to 400mL/min UP200Ht, UP400St
0.1 to 20L 0.2 to 4L/min UIP2000hdT
10 to 100L 2 to 10L/min UIP4000hdT
15 to 150L 3 to 15L/min UIP6000hdT
n.a. 10 to 100L/min UIP16000
n.a. larger cluster of UIP16000

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  • Raquel Martínez-González, Joan Estelrich, Maria Antònia Busquets (2016): Liposomes Loaded with Hydrophobic Iron Oxide Nanoparticles: Suitable T2 Contrast Agents for MRI. International Journal of Molecular Science 2016.
  • Zahra Hadian, Mohammad Ali Sahari, Hamid Reza Moghimi; Mohsen Barzegar (2014): Formulation, Characterization and Optimization of Liposomes Containing Eicosapentaenoic and Docosahexaenoic Acids; A Methodology Approach. Iranian Journal of Pharmaceutical Research (2014), 13 (2): 393-404.
  • Joanna Kopecka, Giuseppina Salzano, Ivana Campia, Sara Lusa, Dario Ghigo, Giuseppe De Rosa, Chiara Riganti (2014): Insights in the chemical components of liposomes responsible for P-glycoprotein inhibition. Nanomedicine: Nanotechnology, Biology, and Medicine 2013.
  • Dayan, Nava (2005): Delivery System Design in Topically Applied Formulations: An Overview. In: Delivery system handbook for personal care and cosmetic products: Technology, Applications, and Formulations (edited by Meyer R. Rosen). Norwich, NY: William Andrew; p. 102-118.
  • Dinu-Pirvu, Cristina; Hlevca, Cristina; Ortan, Alina; Prisada, Razvan (2010): Elastic vesicles as drugs carriers though the skin. In: Farmacia Vol.58, 2/2010. Bucharest.
  • Domb, Abraham J. (2006): Liposheres for Controlled Delivery of Substances. In: Microencapsulation – Methods and Industrial Applications. (edited by Simon Benita). Boca Raton: CRC Press; p. 297-316.
  • Lasic, Danilo D.; Weiner, Norman; Riaz, Mohammad; Martin, Frank (1998): Liposomes. In: Pharmaceutical dosage forms: Disperse systems Vol. 3. New York: Dekker; p. 87-128.
  • Lautenschläger, Hans (2006): Liposomes. In: Handbook of Cosmetic Science and Technology (edited by A. O. Barel, M. Paye and H. I. Maibach). Boca Raton: CRC Press; p. 155-163.
  • Mícková, A.; Tománková, K.; Kolárová, H.; Bajgar, R.; Kolár, P.; Sunka, P.; Plencner, M.; Jakubová, R.; Benes, J.; Kolácná, L.; Plánka, A.; Amler, E. (2008): Ulztrasonic Shock-Wave as a Control Mechanism for Liposome Drug Delivery System for Possible Use in Scaffold Implanted to Animals with Iatrogenic Articular Cartilage Defects. In: Acta Veterianaria Brunensis Vol. 77, 2008; p. 285-280.
  • Ortan, Alina; Campeanu, Gh.; Dinu-Pirvu, Cristina; Popescu, Lidia (2009): Studies concerning the entrapment of Anethum graveolens essential oil in liposomes. In: Poumanian Biotechnological Letters Vol. 14, 3/2009; p. 4411-4417.
  • Ulrich, Anne S. (2002): Biophysical Aspects of Using Liposomes as Delivery Vehicles. In: Biosience Report Vol.22, 2/2002; p. 129-150.
  • Zhu, Hai Feng; Li, Jun Bai (2003): Recognition of Biotin-functionalized Liposomes. In: Chinese Chemicals Letters Vol. 14, 8/2003; p. 832-835.

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Liposomal vitamin C suspension formulated with the Hielscher ultrasonicator UP200Ht

Liposomal vitamin C suspension formulated with the Hielscher ultrasonicator UP200Ht.

High performance ultrasonics! Hielscher's product range covers the full spectrum from the compact lab ultrasonicator over bench-top units to full-industrial ultrasonic systems.

Hielscher Ultrasonics manufactures high-performance ultrasonic homogenizers from lab to industrial size.

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