Overcoming Drug Delivery Obstacles with Nanoemulsions

22 August 2019

GMP News

A large percentage of drugs and NCEs (New Chemical Entity) are insoluble or only poorly soluble in water and, as a result, exhibit poor bioavailability. Since they are often significantly more soluble in oil than in water, one of the most common ways to increase solubilization for these drugs is to formulate them in emulsions, and increasingly in nanoemulsions with mean droplet sizes of 50-100 nm. Examples of drugs formulated into suchemulsions include Paclitaxel, Propofol, Mitomycin, Clarithromicin, Vinorelbine (Exelbine®) and Docetexal (ANX-514).

Whilst conventional emulsions have solubility and stability limitations that can make them difficult to manufacture, nano-emulsions, on the other hand, provide a suitable solution as not only do they show a greatly increased drug load versus conventional emulsions (which allows a reduced dosage to be given to the patient), but they also afford a better stability. In addition, nano-emulsions can be administered subcutaneously, intramuscularly or intravenously, allowing targeted delivery, faster action onset time and often less side effects.

A further factor affecting drug delivery is the need to sterilize emulsions because they are injected inside the body, applied to the eyes, etc. A relatively simple sterilization method is filtration through a 220 nm filter, but if there is a large proportion of particles above 220nm, there will be loss of the active ingredient and the filters may clog. Therefore, not only is the mean droplet size important, but also the droplet size distribution. But, producing a nano-emulsion with a narrow size distribution can be difficult to achieve.

A very efficient way for making nano-emulsions with a narrow size distribution consists of a two-step process: Firstly, the water and the drug-loaded oil phase (with suitable emulsifier and stabilizer) are pre-mixed so that a raw emulsion is created, typically with droplet sizes in the lower micrometer range. This is often done by means of stirring or mixing for example with magnetic, propeller or rotor-stator mixers. In a second step, this raw emulsion is processed through a Microfluidizer® Processor where high shear and impact forces reduce the droplet sizes to the desired sub-micron droplet size.

During the Microfluidizer® process, the raw emulsion is forced through fixed-geometry channels the size of a human hair under process pressures of up to 2000 bar, where it is subjected to extremely high and consistent shear rates. This creates an emulsion that has very small droplet sizes as well as a very narrow droplet size distribution. This enhances both the stability and subsequent sterile filtration capabilities.

Compared with other emulsification methods, the Microfluidizer® process offers several advantages:

Microfluidics International Corp. who manufactures Microfluidizer® processors has a vast experience of delivering cGMP compliant equipment to the pharmaceutical and biotechnological industries, supplying to some of the top pharmaceutical and biotech companies around the world. Several renowned publications have published papers that prove the superiority of Microfluidizer® technology for making nanoemulsions, amongst these is the case study on Corixa where the Microfluidizer® processor was compared to conventional high pressure homogenizers and it was found that:
– the Microfluidizer® consumed 7.5 times less power than the comparison high pressure homogenizer.
– Microfluidizer® emulsions were 18–55% smaller than the ones made on the alternative high pressure homogenizer when run at the same energy input.
– the Microfluidizer® processor created emulsions that were 17–91% less poly-dispersed than the high pressure homogenizer when run at the same energy input.
– the standard deviation of the emulsions created on the Microfluidizer® processor was much lower (0.1–2.6) than with the high pressure homogenizer (3.8–14.8).

In conclusion, the Microfluidizer® process of preparing a nano-emulsion from a coarse premix proves to be a time and energy efficient as well as scalable way of achieving very stable, homogeneous products that can be sterile filtered without significant active losses. In this respect, it plays a vital role in the development and production of formulations of poorly water soluble APIs that allow a targeted delivery and improve bioavailability.




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