Ultramicronization and Nano-Formulation of Palmitoylethanolamide (PEA)

The fatty acid amide palmitoylethanolamide (PEA) is used as oral drug administered for its anti-inflammatory and neuroprotective effects. However, being a lipid and expressing a large particle size, the bioavailability and bioaccessibility of palmitoylethanolamide (PEA) is limited due its poor water-solubility and reduced cellular uptake in the human body. Micronized, ultra-micronized as well as nano-emulsified formulations of palmitoylethanolamide enhance its rate of bioavailability and absorption significantly. Ultrasonic ultra-micronization and nano-emulsification is the superior technique to produce a palmitoylethanolamide (PEA) drug or supplement formulation with excellent bioavailability.

Ultrasonic Ultra-Micronization of Palmitoylethanolamide (PEA)

With ultrasonic milling and dispersing it becomes simple to efficiently and reliable produce ultramicronized N-palmitoylethanolamide (PEA) for pharmaceuticals, nutraceuticals, and dietary supplements. Ultrasonic milling and dispersing allows to reduce the particle size of palmitoylethanolamide (PEA) down to micron- or nano-range. The exact size of palmitoylethanolamide particles can be influenced by the ultrasonic processing parameters such as amplitude, pressure and sonication duration. For instance, a higher amplitude has more disruptive impact on the particles and results in smaller particle size, i.e., ultra-micronized and nano-sized PEA particles.
The oral administration of ultramicronized and nano-sized palmitoylethanolamide (known as PEA-um or ultra-micronized PEA) has been proven to show superior bioavailability and bioaccessibility when compared to larger particle forms. N-palmitoylethanolamide (PEA) particle sizes of 600nm and smaller are ideal for oral administration, especially when encapsulated into liposomes or lipid nanoparticles. Liposomal formulations as well as lipid nanoparticles (i.e., solid lipid nanoparticles (SLN) or nanostructured lipid carriers (NLC)) offer superior effects, which has e.g., by treating inflammatory pain in rat models.

Advantages of Ultrasonic PEA Formulations

  • maximized PEA bioavailability and efficacy
  • ultra-micronized palmitoylethanolamide
  • nano-emulsified PEA formulation
  • pharma-grade production

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Industrial ultrasonic setup with UIP2000hdT for the ultramicronization and nanosizing of palmitoylethanolamide (PEA) for superior bioavailability and health-promoting effects.

The UIP2000hdT is a 2kW powerful ultrasonicator for the ultramicronization and nanosizing of palmitoylethanolamide (PEA). Nanosized PEA shows superior bioavailability and significantly improved effects.

Ultrasonic Milling and Dispersing of Palmitoylethanolamide (PEA)

Ultrasonic particle size reduction is a well established technique, which is used widely in various industries. For instance, active pharmaceutical ingredients (APIs) are often ultra-micronized and nanosized using high-performance ultrasonicators. Therefore, palmitoylethanolamide (PEA) is also often ultramicronized and nanosized using ultrasonication whilst obtaining a pharmaceutical- or neutraceutical-grade product.
Ultrasonically ultramiocronization and nanosizing helps to overcome the drawbacks, which result form the lipophilic and crystalline nature as well as the melting temperature of of palmitoylethanolamide (PEA). The ultramicronized or nano-sized PEA forms allow for the preparation of highly bioavailable drug or supplement formulations.

Ultrasonic Nano-Emulsification of Palmitoylethanolamide (PEA)

Ultrasonic nano-emusification is a basic application, which is required to prepare drug formulatuions with a high bioavailability including liposomes and lipid nanoparticles. The powerful ultrasonic shear forces disrupt lipid and aqueous droplets to such small sizes, that the immiscible liquids become a self-stable nanoemulsion. This process is required for the preparation of liposomes and lipid nanoparticles, where the nanosized lipid droplet is encapsulated into an aqueous coating. This aqueous coating is ideal to transport lipidic active ingredients such as palmitoylethanolamide (PEA) into the cells, where the active substance can take the desired effects (e.g., anti-inflammatory or pain-reducing effects).

Bioavailability of palmitoylethanolamide (PEA) is significantly enhanced when administered in nano-formulations. Ultrasonic encapsulation is ideal to prepare nano-formulated palmitoylethanolamide (PEA).

Structure of palmitoylethanolamide (PEA) and lipid nanoparticles (SLN = solid lipid nanoparticles; NLC = nanostructured lipid carriers).
picture: ©Puglia et al., 2018

Ultrasonically prepared lipid nanoparticles (NPs), such as solid lipid nanoparticles (SLN) or nanostructured lipid carriers (NLC) have been successfully used to improve the bioavailability of orally and topically administered N-palmitoylethanolamide.
One major advantage of ultrasonication is that the ultrasonic technology can not only be used to reduce the mean size of preformed lipid nanoparticles, but also to stabilize the nano-emulsified particle composition for long-term stability. Therefore, sonication plays a key role in controlling the final size and distribution of lipid nanoparticle dispersions and improving the bioavailability of active ingredients such as N-palmitoylethanolamide (PEA).

Ultrasonic Production of Liposomal Palmitoylethanolamide (PEA)

Liposomal PEA formulations show a superior gastrointestinal absorption and overcome the up-take barriers (i.e., poor water-solubility and bioavailability). The oral administration of liposome-ecapsulated palmitoylethanolamide (PEA) results in improved bioaccessibility and to higher plasma levels.
Ultrasonication is a well-established and reliable method to produce liposomal formulations in small and large quantities. Ultrasonic liposome production is known for a high encapsulation efficiency (%EE) and long-term stability. Therefore, sonication is already used for liposome production in pharmaceutical, nutraceutical and cosmetic production.
Learn more about the advantages of ultrasonic liposome encapsulation!

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High-Performance Ultrasonicators for Nanosizing Palmitoylethanolamide

Hielscher Ultrasonics is your trusted partner when it comes to high-performance ultrasonicators for ultramicronization, nanosizing and nano-encapsulation of palmitoylethanolamide (PEA). Since Hielscher Ultrasonics’ industrial ultrasonic processors easily deliver very high amplitudes of up to 200µm in continuous 24/7 operation, they are reliably capable to produce ultra-micronized and nano-sized N-palmitoylethanolamine (PEA). The same ultrasonic system used for ultramicronization and nanosizing can be used in the subsequent preparation of PEA-encapsulating nanoemulsions, liposomes and lipid nanoparticles.
As Hielscher’s product portfolio covers the full range from compact, yet powerful lab ultrasonicators to fully-industrial production systems, we can offer you the ideal ultrasonic homogenizer for your application and production goals. Numerous accessories such as sonotrodes (also known as ultrasonic probes or ultrasonic horns), booster horns, flow cells and reactors allows to configure the optimal ultrasonic setup for superior outcomes.
Contact us know! Our well-trained and long-experienced staff will be glad to give you more information and recommend you the right ultrasonicator for your palmitoylethanolamine (PEA) process!

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

Batch Volume Flow Rate Recommended Devices
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
n.a. 10 to 100L/min UIP16000
n.a. larger cluster of UIP16000

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Ultrasonic high-shear homogenizers are used in lab, bench-top, pilot and industrial processing.

Hielscher Ultrasonics manufactures high-performance ultrasonic homogenizers for mixing applications, dispersion, emulsification and extraction on lab, pilot and industrial scale.

Literature / References

Facts Worth Knowing

What is Palmitoylethanolamide?

Palmitoylethanolamide (PEA) or N-palmitoylethanolamide is an endogenous fatty acid amide, which means it is a substance that the human body can manufacture by itself. Palmitoylethanolamide has attracted a lot of attention in the medical field as a potent treatment of pain and inflammation. PEA can be also found in foods such as eggs and milk and no side effects or negative drug-drug interactions have been observed so far.
As a lipidic molecule, the poor water-solubility and thereby poor bioavailiability of N-palmitoylethanolamide is a major challenge for its therapeutic use. Since, palmitoylethanolamide is almost insoluble in water and very poorly soluble in most other aqueous solvents, palmitoylethanolamide requires a sophisticated formulation, including ultramicronizing and encapsulating the palmitoylethanolamide molecules into a nanoemulsion or lipid nanocarriers. Ultrasonication is an established technique for the reliable and efficacious ultramicronization and nano-formulation of palmitoylethanolamide.

Other terms used for palmitoylethanolamide: N-palmitoylethanolamide, Hydroxyethylpalmitamide, Impulsin, N-(2-Hydroxyethyl) hexadecanamide, N-(2-Hydroxyethyl)palmitamide, Palmidrol, Palmitamide MEA, Palmitic Acid Monoethanolamide, Palmitoylethanolamine.

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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