Hielscher Ultrasound Technology

Ultrasonic Nano-Encapsulation of Ivermectin

Drugs such avermectin and ivermectin are often encapsulated into nano-structured drug carriers to improve absorption rate and bioavailability as well to obtain a sustained‑release effect. Ultrasonic nano-emulsification is an efficacious and reliable technique to entrap bioactive medicinal compounds into solid-lipid nanoparticles, liposomes or cyclodextrin complexes.

Ivermectin

Ivermectin, a member of the avermectin drug class, is an anti-parasitic drug used mostly to treat roundworm infections. It works by by binding to and activating glutamate-gated chloride channel receptors (GluClRs) of the parasites, thereby paralyzing and killing them. During the research for a cure against COVID-19, the disease caused by the novel coronavirus SARS-CoV-2, ivermectin came into the focus of pharma research as it killed the SARS-CoV-2 coronavirus within 40hr in “in vitro” tests. Aa an already FDA-approved drug, the pharmacology of ivermectin is well known and the drug would be readily available for fast implementation of COVID-19 mass treatment. (status Apr, 12th 2020).

Ultrasonic Encapsulation of Ivermectin

Nano-sized drug carriers such as solid-lipid nanoparticles (SLNs), liposomes and cyclodextrin complexes are known to improve drug delivery and bioavailability, to provide a slow / sustained drug release, and to protect the bioactive molecule against degradation. As ivermectin is incompatible with various common excipients, which requires an alternative formulation. Furthermore, ivermectin is prone to be degraded by light, oxygen and hydrolysis, so that encapsulation helps to protect and stabilise the drug compound. Solid-lipid nanoparticles, liposomes or cyclodextrin-based ivermectin formulations show good results offering protection against degradation as well as improved solubility and stability.
The ultrasonically prepared ivermectin-SLNs showed a relatively high encapsulation efficiency (EE) with a narrow particle size distribution. The release study displayed slow and sustained release patterns for ivermectin-SLNs.

Ultrasonic processor UIP2000hdT (2kW) with stirred batch reactor

Ultrasonic homogenizer UIP2000hdT (2kW) with continuously stirred batch reactor

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Ultrasonic Encapsulation of Ivermectin in Solid-Lipid Nanoparticles

Ultrasonically promoted formation of solid-lipid nanoparticles is a well-known technique used to formulate pharmaceutical complexes with a high absorption rate and bioaccessibility, low cytotoxicity, and sustained drug release.
Guo and coworkers (Guo et al. 2017) showed in their research that ultrasonic encapsulation of ivermectin in solid-lipid nanoparticles (SLNs) resulted in amorphous ivermectin particles within the SLNs and displayed prolonged release of the drug molecules from the SLNs without burst release due to high encapsulation efficiency (EE).
The preparation of ivermectin SLNs was performed in order to the following protocol:
SLNs were prepared by hot homogenisation, followed by ultrasonication. Briefly, palmitic acid (0.5 g) was melted in a 30-ml glass vial by a magnetic stirrer at 75ºC. Ivermectin (0.09 g) was then dissolved in the melted lipid. The lipid phase was subsequently poured into 15mL of boiling aqueous solution with 1% PVA (w/v) under magnetic stirring at 300rpm for 10 min to form a coarse oil-in-water emulsion. After that, the emulsion was sonicated for 5 min, and then 15 mL of cold water (4ºC) was immediately poured into to obtain the ivermectin-SLNs. Control SLNs were prepared following the same protocol without the addition of ivermectin.

Liposomal Avermectin Formulation

Liposomes are composed from one or more phospholipid bilayers. Combining chemically and biologically inert synthetic polymers to produce long-circulating liposomes allows for the preparation of liposomes with prolonged drug circulation time in vivo, thereby enhancing the effectiveness. For example, the duration of efficacy of liposomal avermectin was increased from 21 to 30 days in goats (Sun et al., 2014).
Besides the formulation into solid-lipid nanoparticles, ivermectin has been successfully encapsulated into liposomes and cyclodextrin complexes.
Read more about the ultrasonic formulation of liposomes and cyclodextrin complexes!

Ultrasonication is a fast and reliable technique to produce superior nano-liposomes.

UP400St, a 400 watts powerful ultrasonic homogeniser, for the production of liposomes and SLNs

The Advantage of Ultrasonic Lipid Nanoparticle Preparation

  • High performance emulsification
  • Exact control over lipid particle size and load
  • High load of active substances
  • Exact control over process parameters
  • Fast Process
  • Non-thermal, precise temp control
  • Linear Scalability
  • Reproducibility
  • Process standardisation / GMP
  • Autoclavable probes and reactors
  • CIP / SIP

High Performance Ultrasonicators

High-Performance Ultrasonicators for Pharma Formulations
Hielscher Ultrasonic is long-time experienced in the design, manufacturing, distribution and service of high-performance ultrasonic homogenisers for the pharmaceutical and food industry.
Precise control over the ultrasonic process parameters by Hielscher Ultrasonics' intelligent softwareThe preparation of high-quality liposomes, solid lipid nanoparticles, polymeric nanoparticles and cyclodextrin complexes are processes, which Hielscher ultrasonic systems are used with high reliability and superior quality output. Hielscher ultrasonicators allow for precise control over all process parameters, such as amplitude, temperature, pressure and sonication energy. The intelligent software automatically protocols all sonication parameters (time, date, amplitude, net energy, total energy, temperature, pressure) on the built-in SD-card.
The robustness of Hielscher’s ultrasonic equipment allows for 24/7 operation at heavy duty and in demanding environments.
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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Hielscher Ultrasonics manufactures high-performance ultrasonic homogenizers for dispersion, emulsification and cell extraction.

High-power ultrasonic homogenizers from lab to pilot and industrial scale.

Literature/References



Facts Worth Knowing

Ivermectin

Ivermectin is a mixture containing at least 90% 5-O-demethyl-22,23-dihydroavermectin and less than 10% 5-O-demethyl-25-de(1-methylpropyl)-22,23-dihydro-25-(1-
methylethyl)avermectin, generally referred to as 22,23-dihydroavermectin.
Ivermectin is available as a generic drug in a 3mg tablet formulation. Common brand names of ivermectin are Driponin and Scrabioral in Germany, Heartgard, Sklice and Stromectol in the United States, and Mectizan in Canada to name just a few.

Avermectin

Avermectins are disaccharides (ivermectin, doramectin) or monosaccharides (selamectin). Avermectins are a series of macrocyclic lactone derivatives with antiparasitic effects, mainly used to treat nematode infections. Insoluble in water, avermectin can be solubilised in methanol and 95% ethanol.