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Dear All,
We are developing a LC-MS/MS method to support PK studies of nanoformulated small molecules. In literature, methods for such purposes used free drug for calibration and validation. However, if the extraction recovery is different for the free drug and the nanoparticle-bound drug, and yet the free drug was used to make the calibration curve, this obviously will give false results.
Any thoughts? or can you refer to any publications in that regard?
Thank you
Nagsen Gautan
Department of Pharmaceutical Sciences
University of Nebraska Medical Center
Omaha, NE 68198-6025
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Dear Nagsen,
If you consider your nanoformulation as a prodrug which harbors an inactive drug when encapuslated and drug is active only upon release, it would be rational to estimate free released drug, drug encapsulated inside the nanoformulation and the sum total which is encapsulated + released drug after administration. The free released drug in my opinion without any doubt can be correlated with the calibration curve made out of free drug following a particluar extraction procedure. Now, we have problem with estimation of nanoformulation bound drug and sum total drug. You are right, it is not appropriate to correlate it with the calibration curve made out free drug the used above. Alternatively, you can change the extraction procedure for making calibration curve of free drug in such way that it is same as the one used to measure nanoformulation bound drug and sum total drug. This would probably ensure you are getting right numbers in terms of concentration of drug. I hope I addressed your question.
I would like to suggest the following article which supports the issue under discussion.
1. Pharmacokinetic study of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced malignancies.
Zamboni WC, Strychor S, Maruca L, Ramalingam S, Zamboni BA, Wu H, Friedland DM, Edwards RP, Stoller RG, Belani CP, Ramanathan RK.
Clin Pharmacol Ther. 2009 Nov;86(5):519-26. Epub 2009 Aug 12.
Thanks for sharing your question.
Kashyap
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That's why you do the recovery assay. if you can destroy your nanpparticle completely and extrct your drug from matrix more than 70 percent.
That's should be fine.
chang
Department of Biochemistry
UT Southwestern Medical Center
5323 Harry Hines Boulevard
Dallas, Texas 75390-9038
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Dear Nagsen Gautan
In general, this case applies not only to nanoparticles, but also for each and every formulation. Due to the extraction recovery difference between pure drug and drug in formulations, we generally determine the extraction recovery of the method. To do this, spike the pure drug in placebo formulation and compare the response with pure drug. Sometimes, the drug can be spiked at different concentration levels to construct a calibration curve and unknown samples concentration can be calculated from this.
In case of nanoparticles, you can easily achieve higher extraction recoveries (> 95%) eby digesting them (sonication) with acetonitrile or acetone for 15-30 min.
Hope this helps
Best Regards
Sivacharan Kollipara Scientist Pharmaceutical and Analytical Development Novartis Pharmaceuticals Hyderabad India
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