A Solution at Last!
After finalizing Miglyol 812 N as the primary solvent for our TMZ nasal spray formulation last week, I couldn’t help but wonder if there was a way to make the solution even better– especially considering the possibility of binary, ternary, and quaternary solvent systems.
Looking for answers, I turned to the standard protocol for selecting a solvent for lipophilic molecules to finish what I had started. This led me to the final step – experimenting with several lipids.
We ultimately finalized the lipid Labrasol (PEG-8 Caprylic/ Capric Glycerides). Labrasol’s function as a surfactant, increases the solubility of the solution, as it helps TMZ dissolve in Miglyol by creating nanoemulsions. Nanoemulsions are small, dispersed droplets or bubbles instead of a viscous steam of large oil droplets, which provides several benefits.
- Increased drug absorption: The small particles allow the solution to bypass tight junctions in the nasal epithelial cells. (This is why Labrasol is known as a permeation enhancer.)
- Increased surface area: Several small spherical molecules have a greater total surface area than one large molecule of the same volume.
- Increased Stability: By preventing the coalescence of oil droplets, Labrasol helps maintain monodisperse particle size, crucial for consistent drug delivery .
With the TMZ better dissolved and dispersed, we prevent precipitation in the solution. Studies have also shown that, for these reasons amongst others, nanoemulsions improve nose-to-brain transport via the olfactory and trigeminal pathways.
With a Temozolomide + Miglyol + Labrasol solution at hand, I wanted to further improve the solubility and sprayability of the solution. Taking a trip into the past, I revisited one of the first formulations I had tried: Propylene Glycol (PG) + Polyethylene Glycol 400 (PEG 400).
I noted that this solution had great solubility, however it sprayed like a jet due to the viscosity provided by PEG 400. So, I decided to isolate just PG and use it as a co-solvent and permeation enhancer to solubilize TMZ, increase the density of the solution to prevent the nanoemulsions from entering and irritating the lungs, and help the solution spray more like a mist since PG is much less viscous than oil. Furthermore, the necessary viscosity is already being provided by the PEG within Labrasol. Additionally, PG moisturizes the nasal passages and stabilizes the nanoemulsions, to prevent them from disassembling when they reach the water-based parts of the brain.
Now you may have noticed that in addition to their many roles, Labrasol and PG function as permeation enhancers, which (you could probably tell by the name) improve absorption.
In efforts to increase permeability once more, we tried a variety of permeation enhancers before settling at Transcutol HP mainly for its safety and effectiveness. Transcutol HP…
- Ensures stability in the formulation, as it is compatible with the other ingredients
- Is recognized as safe for nasal and topical formulations
- Has low toxicity
- Is mild and non-irritating, making it perfect for sensitive areas like the nasal cavity
- Is effective at low concentrations, mitigating any potential side effects
- Is non-volatile, ensuring physical and chemical stability for the duration of the shelf life
After lots of trial and error… WE FINALLY HAVE A BASE SOLUTION! A 50:30:10:10 ratio of Miglyol, Propylene Glycol, Labrasol, and Transcutol HP, respectively! It’s officially time to kick off Phase 2 of testing: Stability Studies! Cue the victory dance!