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The following message was posted to: PharmPK
Dear all,
I need to know the class of Biopharmaceutical classificaiton system in
which Eplerenone belong to proceed for the solubility enhancement as
my project work
I searched the internet, but couldnt find any relevant material. If
anyone can suggest some means of finding this information, It would be
of great help to me.
Thanks in advance,
Regards
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The following message was posted to: PharmPK
See "Spironolactone" What do you mean by "Class of Biopharmaceutical
Classification"? It is a steroid, an antagonist of aldosterone.
--
Ed O'Connor, Ph.D.
Laboratory Director
Matrix BioAnalytical Laboratories
25 Science Park at Yale
New Haven, CT 06511
Web: www.matrixbioanalytical.com
Email: eoconnor.at.matrixbioanalytical.com
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The following message was posted to: PharmPK
Hi,
There's a quadrant-style classification system industry tends to use
(called the "Biopharmaceutics Classification System"):
Class 1: high permeability, high solubility
Class 2: high permeability, low solubility
Class 3: low permeability, high solubility
Class 4: low permeability, low solubility
There's a more rigorous definition of the BCS on the FDA website:
http://www.fda.gov/cder/OPS/BCS_guidance.htm
Ashish wanted to know which BCS class spironolactone fell into, not
the drug class. According to Les Bennet, it's Class 2:
http://www.aapspharmaceutica.com/meetings/files/103/LesBenetChallengesRoundtableinBCS.pdf
Hope this helps,
-Dave
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Eplerenone is a classic example of the fact that molecules cannot be
classified into BCS classifications. Only formulations can be
classified into BCS classes.
We use a combination of biopharmaceutical property estimation and
gastrointestinal simulation to help define the BCS classification. I
did not do a literature search for the experimental properties of
eplerenone but I spent about 5 minutes doing the in silico
calculations. Someone on this list will probably do the search to
confirm or refute the calculations.
Eplerenone is a neutral steroid with six hydrogen bond acceptor
oxygens. The combination of hydrophobicity and hydrogen bonding make
it a border line molecule.
According to ADMET Predictor (Simulations Plus, Inc.) eplerenone has:
log P = 1.9
Human effective permeability = 1.97 x 10^-4 cm/s
Water solubility = 0.015 mg/mL at pH 7.0.
Using those properties in a GastroPlus simulation at a dose of 1 mg/mL
with particle size of 5 microns we estimate 98% absorbed. A dose of 1
mg is well below (only 26%) of the amount that will dissolve in 250 mL
of water (3.825 mg) at the lowest solubility between pH 1 and pH 7.5.
According to the FDA:
"A drug substance is considered HIGHLY SOLUBLE when the highest dose
strength is soluble in < 250 ml water over a pH range of 1 to 7.5" and..
"A drug substance is considered HIGHLY PERMEABLE when the extent of
absorption in humans is determined to be > 90% of an administered
dose, based on mass-balance or in comparison to an intravenous
reference dose."
Therefore, eplerenone is classified as BCS Class I by our software. OR
IS IT?
At a dose of 10 mg/mL with particle size of 5 microns we estimate 97%
absorbed. But now the dose of 10 mg is well above (Dose Number = 2.6)
the amount that will dissolve in 250 mL of water (3.825 mg) at the
lowest solubility between pH 1 and pH 7.5.
Therefore, eplerenone is classified as BCS Class II by our software.
OR IS IT?
At a dose of 10 mg/mL with particle size of 25 microns we estimate
only 67% absorbed. Here, the larger particle size slows the
dissolution resulting in 38% being absorbed in the colon. The Dose
Number still says that 10 mg is 2.6 times the amount that will
dissolve in 250 mL of water.
Therefore, eplerenone is classified as BCS Class IV by our software.
NOTE that the permeability of 1.96 x 10^-4 cm/s alone does not result
in high permeability classification. It is generally agreed that if a
molecule has permeability greater than metoprolol (1.34 x 10^-4 cm/s)
it is highly permeable. However, as this example illustrates, only the
integrated values that result in a predicted fraction absorbed result
in a correct classification.
My point is NOT that in silico calculations can replace in vitro
assays or that the BCS Classification system is flawed. On the
contrary nothing can replace experiments when you want to get to the
most accurate answers from simulation technology. The BCS
Classification system or the BDDCS are very valuable for pointing out
the primary issues of biopharmaceutical properties, metabolism, and
transport to consider when deciding on clinical candidates and
formulations.
My point is that we all need to begin to integrate our complete sets
of data and try to understand the detailed mechanism and interactions.
Modeling and simulation is one way to do this.
Biowaviers hang in the balance. If you want to read more about
simulations and Class II BCS compounds being eligible for biowaviers
please read:
Tubic-Grozdanis M, Bolger MB, Langguth P.
Application of gastrointestinal simulation for extensions for
biowaivers of highly permeable compounds. AAPS J. 2008;10(1):213-26.
Epub 2008 Apr 2.
Also, a group of speakers from industry, academia, and the FDA will be
presenting a Short Course on Sunday November 16th from 8:30 to 4:00 at
the AAPS meeting in Georgia entitled "Application of Biopharmaceutics
in Modeling and Simulation". Please check it out.
Thanks,
Mike
* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *
* Michael B. Bolger, Ph.D.
* Chief Scientist
* Simulations Plus, Inc.
* 42505 10th Street West
* Lancaster, CA 93534
* U.S.A.
* http://www.simulations-plus.com (NASDAQ: SLP)
* bolger.aaa.simulations-plus.com
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The following message was posted to: PharmPK
Perhaps this article may be of some use for you.
LinksCook CS, Berry LM, Bible RH, Hribar JD, Hajdu E, Liu W.
Pharmacokinetics and metabolism of [14C]eplerenone after oral
administration to humans.
Drug Metab Dispos. 2003 Nov;31(11):1448-55.
Thanks
Lavit Jambu
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