Back to the Top
I am working to solubilize a lipophilic compound. I solubilized the
compound in DMSO then added molten TPGS. The drug/DMSO/TPGS solution
was then added to water heated to 60 degrees with shaking to a final
TPGS concentration of 20% (v/v) and DMSO (4%). The solution is a
milky pearlescent emulsion that remains an emulsion for several
hours. Without shaking, at room temperature, the solution eventually
separates into a clear liquid and fine particles on the bottom of the
vial. If the separated material is shaken, the solution again turns
to a milky emulsion. Is this considered a successful emulsion, or a
failure? Is a 20% (v/v) TPGS solution in water for injection safe
for repeated oral administration (daily for 28 days)?
Thanks for any guidance of information.
Steve
Back to the Top
Vitamin E TPGS is a speciality excipient and known as d-Alpha-
Tocopheryl Polyethylene Glycol-1000 Succinate. A type IV DMF 12715
for Eastman vitamin E TPGS NF is on file at the United States FDA.
This excipient is official in Euroean pharmacopoeia and used in
cosmetics preferentially. Oral LD 50 in rats is >7000mg/kg. The
result of one year incubation studies with rats and dogs conducted by
National Cancer Institute indicate that there are no safety issues
upto 1000 mpk in either species. However these results are just
informatory and are indicated not to be used for reference purpose by
the supplier. No chronic IV administration data is currently
available by the supplier.
Moreover, to my information only Amprenavir (Agenerase(R)) is
available as an approved product using TPGS as an speciality
excipient. TPGS seem to influece both solubility and permeability (p-
gp mediated) and hence a judicious decision making is warranted using
excipients like this in animal proof of concept and/or safety
evaluation stages. The exact procedure of formulating is provided at
the site of the supplier in varius publications. The best way however
could be to use a phase solubility curve to avoid any precipation
potential of a supersaturated solution prepared from using TPGS.
I would appreciate experiences of fellow formulation scientis on the
use of this excipients.
regards,
Dr. Vaibhav Sihorkar
Senior Scientist, FRD
Discovery Research
Dr. Reddy's lab Ltd., Hyd, INDIA
+91-9391627107
Back to the Top
Why use DMSO? It's nearly impossible to remove from your solution
after the fact due to its high boiling point. I wonder if the DMSO,
even at 4% is disrupting your emulsion, although I think unlikley.
Ultimately what you have here is what I would describe as a
macroemulsion, which in of itself is not very stable, unlike
microemulsions. I would describe the phoenomenon you see as
coalescence or flocculation, depending on how one chooses to define
these terms. There are a variety of methods to overcome this but it
boils down to trial and error. Have you thought about adding a
surfactant of some type to help stablize the surface of the oil
droplets?
Regards,
Phil
Back to the Top
I need a final concentration of 10-20 mg/ml so I needed a relatively
high drug concentration initially in TPGS before dilution with
water. The compound was poorly soluble directly into molten TPGS.
Because the compound is highly soluble in DMSO I tested adding DMSO-
solubilized drug to molten TPGS which occurred without
precipitation. I also considered using PEG400 or DMA to solubilize
the drug prior to TPGS, but have not yet evaluated drug solubility in
these solvents.
As for surfactants I could try 0.2% Tween 80 or Cremophor for
positive effects on stabilizing the oil droplets.
I welcome any other suggestions/comments.
PharmPK Discussion List Archive Index page
Copyright 1995-2010 David W. A. Bourne (david@boomer.org)