Dear Sir. Concerning your issue about the application of Cyclodextrin derivatives for the Clinical use. Cyclodextrins (CDs) are a family of cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity. CD molecules are relatively large with a number of hydrogen donors and acceptors and, thus in general, they do not permeate lipophilic membranes. In the pharmaceutical industry, CDs have mainly been used as complexing agents to increase aqueous solubility of poorly soluble drugs and to increase their bioavailability and stability. CDs are used in pharmaceutical applications for numerous purposes, including improving the bioavailability of drugs. Current CD-based therapeutics is described and possible future applications are discussed. CD-containing polymers are reviewed and their use in drug delivery is presented. Of specific interest is the use of CD-containing polymers to provide unique capabilities for the delivery of nucleic acids. Studies in both humans and animals have shown that CDs can be used to improve drug delivery from almost any type of drug formulation. Currently, there are approximately 30 different pharmaceutical products worldwide containing drug/CD complexes in the market. I think the following below links may help you in your analysis:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3147107/

http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.6.3654&rep=rep1&type=pdf

https://notendur.hi.is/thorstlo/general.pdf

https://link.springer.com/article/10.1007/BF01041363

Thanks

Hi Prashant,

 I am afraid that the feedback above contains only general remarks and they do not helpt to you too much.

From your side the "clinical use" needs some more explanation. For human use, in sample preparation, or in cell cultures?

 Citric acid derivatives of beta-cyclodextrin are esters. Because the ester bond is chemically unstable in living organism (and chemically in basic solutions) the parenteral use of bCD esters should be studied case by case. Please, also note that the citric acid derivative is a randomly substituted material and the reproducibility of the results are heavily questioned.

 Human use

 Usually bCD derivatives are recommended for oral administration only because this CD can form crystalline complexes with many compounds, and the pin-like bCD/cholesterol complex can serious damage in kidneys (cholesterol is sequestered from the cells).  Those derivatives which practically do not form poorly water soluble complexes, like (2-hydroxy)propyl-bCD (HPbCD), sulfobutylated-bCD (SBbCD), and methylated bCD can also be administered parenterally, although currently only HPBCD and SBbCD are allowed for parenteral use, because of the high affinity of the methylated version toward cholesterol (in vitro this type of derivatives have serious haemolytic activity). HPBCD is a good host molecule, it can form complexes with many pharmacons, while complexation ability of the more hydrophilic SBbCD is very limited. 

 Because sample preparation is not connected to living patients there are no reason to refuse its use. The use of citric acid bCD conjugate for analysis, owing to its random structure, may be difficult because of some reproducibility issues.

 The use citric acid-bCD conjugate for cell cultures is in the middle: it is necessary to study its effect to the cell cultures but there is no theoretical limit.

Good luck,

Laszlo

Very Very Thanks, Laszlo.

Your provided information is supportive.

I willing to use  Citrate BCD derivative for Oral medicinal preparation only.

Have their is any concern for  stability and any kind of Toxicological concern?

Hi Prashant,

 I do not know the current situation of citric acid bCD conjugate, but I am afraid that has not been accepted - yet - as excipient. That is a long process.

 The citric acid is not toxic and bCD is approved in numerous countries for oral drug delivery, in relatively high CD doses. That means the conjugate has a great opportunity not to be toxic, but I have poor information on toxicologic studies of this derivative, sorry.

 Because the esters are also hydrolyzing in acidic environment, you can perform a simple and fast experiment to check what might happen. Dissolve the citric acid bCD conjugate in a artificial gastric acid and test the solution periodically. The appearance of bCD and/or glucose on TLC (or in HPLC chromatograms, but that is more expensive and slower) indicates the decomposition of the ester. On TLC you can use alcoholic H2SO4 for the visualization (spry the plate with it then heat it at ~100-110 oC). Citric acid is not charred while both the CD and (the conjugate also) and glucose (hydrolysis product of CD) are charrable. In diluted HCl solution the CD degradation is slow, but the further hydrolysis is considerably faster, but I am almost sure that the citric acid ester hydrolysis is faster than the CD degradation.

 If the conjugate is destroyed in the artificial gastric acid that is a good safety argument.

 If you need further details, just contact me.

Good luck,

Laszlo

Dear Laszlo,

I have issue with yield of the Water soluble citrate bCD derivative,

Can you share the manufacturing process to prepare the citrate BCD derivative to get good yield.