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Dear all
I'm now doing the pharmacokinetic study of a water insoluble compound. For the i.v. administration, I tried to solubilize the compound in aqueous solutions. I used the PEG400, Tween-80, Tween-20, Pluronic F-68 etc, but all of them cannot achieve to the satisfied concentration of the compound (<1 mg/mL).
Therefore, can I use the DMSO or DMA as a solubility ehancer in the i.v. injection? And what is the Max. concentration I could use for them?
I'm very greatful if someone can give me any suggestions and references about this!
Happy new yaer to everyone!
--
Best Regards,
Alec H YU
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Dear Alec,
You can refer to the ICH residual solvent limit and find out the maximum allowable limit for these type of solvents. Also you can see the LD50 and toxicological data (that is available on the net) and can do your studies.
With Regards,
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Dear Alec,
Some idea you can get from
http://www.emea.europa.eu/pdfs/human/ich/028395en.pdf
Busulfan Injection is approved by FDA, in which DMA used as solvent.
Regards,
Dr. Tushar Rajyaguru
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The following message was posted to: PharmPK
Alec,
Can you disclose the approximate molecular weigh and type of structure
of the compound for solubilization? Is this a natural product or
totally synthetic small molecule? Depending on your answer there are
several ways to approach the solution.
Thank you,
Ving J. Lee
SVP research and CSO
Limerick Biopharma, Inc.
South San Francisco, CA. 94080
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Alec,
what is the species into which you are going. DMSO can be used however, there is a hemolysis issue that you will need to contend with in your bioanalysis. Have you thought of HPBCD or Peg:Ethanol:water mixtures to facilitate and obviate DMSO. There are also lipid injectables, depending on the species of interest that may be used.
-- Sanjeev Thohan, PhD
SARx Consulting
SARxconsult.-a-.Gmail.com
http://www.linkedin.com/in/sanjeevthohan
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Dear Dr. Sanjeev
Our compound is a water-insoluble Diterpenoid purified from the herbal medicine.
Now I'm doing the PK profile of that compound. To evaluate its absolute bioavailabilities after ip, po administration, I should do the iv PK first. But the solubility of the compond is too low in water, I hope to solubilize it in the aqueous solution for iv injection to rats.
I'm very grateful if you can give me some advice on it.
Thank you very much!
--
Best Regards,
Alec H YU, Ph.D.
Research Associate
Institute of Chinese Medicine
2/F, Science Centre East Block
The Chinese University of Hong Kong,
Shatin, N. T.
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The following message was posted to: PharmPK
Alec,
Have you consider the following:
1) Solubilization in Captisol (works miracles when it works, one has to
try empirically). I have a unique way to solubilize lipophilic natural
products in Captisol)
2) 15% ethanol / 50% DMSO / 35% PEG400 (just to be on the safe side, do
a vehicle control arm in any studies with this formulation)
3) Cremaphor-like incipients (even though there is a lot of work done
with this solubilization factor, one has to be careful for it can
confound data analysis--so be careful)
I personally do not like DMSO, DMF or DMAC for dosing because animal
responses are species-dependent.
Regards again,
V. Lee
CEO-CSO
Adesis Inc.
New Castle, DE 19720
and
SVP Research and CSO
Limerick BioPharma Inc
South San Francisco, CA 94080
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In an earlier message Ving Lee had some nice suggestions for formulations that can be readly used. Trying to keep a good aqueous content balance is a key. You can dose up to 100 uL of IV DMSO in rats (total blood volume 10-14 mL), but you will face hemolysis in the blood samples. If you can manage this analytically it may provide a starting point without extensive formulations development. Using lipid solubilizers like labrasol and labrafac maybe an alternative, capryol and even corn oil suspensions can be used on very low volumes.
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The following message was posted to: PharmPK
Dear Alek,
There have been many discussion chapters in PharmPK covering the similar objectives in last couple of years. You can visit to PharmPK archives and look for terms like "solubility" or "oral bio-availability enhancement" etc, and you are bound to get valuable insights.
Coming to your question floated few days back, as being said earlier by colleagues on this forum, avoid as far as possible co-solvent based approach as it may not necessarily reflect the PK profile that your compound may intrinsically offer. Most of the compounds dissolve in co-solvent(s) in a log-linear fashion (i.e., more than proportional increase in solubility beyond a certain strength) and tend to (nano)-precipitate upon dilution and hence what you may get eventually is a PK profile of re-dissolved compound over a period of time in circulation. On contrary, when you dose your compound orally, it will reach to systemic circulation in a dissolved/soluble form, and hence PK profile is dictated by dissolved fraction (rather than precipitated one) and may not necessarily coincide with IV PK obtained from a co-solvent based approach.
General guideline that makes sense to a pharmaceutical development team rely on ionization constant and partition coefficient of your compound and should follow (based upon your physicochemical interpretation) a pH modification/micro-environment pH/salt/ion pair (g1), complexation (g2), (g1+g2), solubilizers within NOEL and NOAEL for specific animal species (g3), (g1+g3), co-solvent alone or in combination within NOEL or NOAEL for specific animal species (g4), (g1+g4), (g1+g5) or (g1+g6), or a combination thereof. In any of these cases, check dilution potential 1:5 or 1:10 v/v/ of your co-solvent solution by in vitro testing using IV relevant fluid/ buffer) along with osmolality measurement, which should be kept within certain limits of ~300 mOsmoles and pH within preferably 4.0 to 9.0.
Hope this will help.
regards
Vaibhav Sihorkar, Ph.D.
[Head, Pharmaceutical Development]
Aurigene Discovery Technologies Limited
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Dear Alec,
Have you considered to develop a solid or colloidal nanoformulation of your compound? It is a relatively quick process and the lower the aqueous solubility of your compound is the greater the solubility improvement you can achieve. In one example a compound has an aqueous solubility Cmax of approx. 0.0034 mg/ml which went up by 125 times by nanoformulation. This also brought forward the Cmax by 60 mins, pushed up the Cmax and AUC by 7 times.
Best Regards,
Gabor
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