This post examines a TessMed product that might be modified for valproic acid. Chitosan and Dextrin are not clay binders but they can form bonds with therapeutic short chain fatty acids.
Ingredients CyLoc alpha dextrin fiber matrix, butyric acid complex, plant amylase. Stabilized Butyric acid as soluble, pure, individual free fatty acid in a hexadextrin matrix molecular trap compounded with DexKey release agent (patent pending, Al Czap, Czap R&D, licensed by Tesseract Medical Research, LLC). CyLoc and DexKey are trademarks of Tesseract Medical research, LLC.
What is alpha dextrin?
Alpha dextrin is another name for cyclodextrin. Make note of those –OH groups radiating from the sides of the molecule. Note the structures of butyrate and avalerate whit the two Oxygens on the left ends. One of these can “come off” to form H2O with cyclodextrin to form what we call an ester bond. Also note the structure of chitosan, a compound we had been looking at as a therapeutic. Note that some of the Nitrogens in this structure have two Hydrogens. Chitosan was requested to be examined with other bile acid binders. Cholic acid is a simple bile acid. One of these can donate an H to combine with an OH from butyric acid or valeric acid.
Note: These images contain the “conjugate base” of butyric and valeric acids. The acid for has an “H” where there is an O– in the structure. Whether or not there is an O– or and OH depends on the pH. Make close note of the ester bond. An esterase is an enyzme that takes esters back to the original alcohol and acid.
What about free short chain fatty acids in the stomach?
The conjugate bases of short chain fatty acids are 50% in the protonated acid form below their pKa. The following are pKa of intestinal short chain fatty acids from Wikipedia
- acetate, pKa pKa 4.76
- propionate, pKa 4.88
- butyrate, pKa 4.86
- valerate pKa 4.82
Can the protonated, forms of these short chain fatty acids simply diffuse across the apical membrane of epithelial cells of the stomach and then lose a proton in the intracellular environment around pH 7.5?
Making Short chain fatty acid conjugates [1,2]
We are returning to the concept of esters and amides…
Butyric acid cyclodextrin ester conjugates for colonic delivery
Hirayama and coworkers published a protocol over 20 years ago.  This is a summary of the abstract not intended to be an in depth report. The authors loaced beta beta-cyclodextrin with butanoic acid as an ester, see Figure 1. It’s hydrolysis was subsequently investigated in aqueous solutions and in rat intestinal fluids.  Enzymatic hydrolysis was investigated using alpha-amylase and esterase . The authors mentioned a V-shaped pH profile, indicating a specific acid-base-catalyzed hydrolysis at acidic and neutral-alkaline regions, respectively.  The half-lives (t1/2) of the conjugate at pH 4.4, 6.8, and 7.4 at 37oC were approximately 580, 43, and 6 days, respectively, indicating that the conjugate is stable in aqueous solution. No appreciable release of n-butyric acid from the conjugate was observed in the stomach and small intestinal contents of rats, or in the small and large intestinal homogenates of rats. 
On the other hand, a fast disappearance of the conjugate and an appearance of n-butyric acid were observed in the cecal and colonic contents of rats. The t1/2 values of the disappearance were approximately 4, 1, and 6 h in 10 and 15% cecal contents and 10% colonic contents, respectively, and the appearance of n-butyric acid after 6 h was approximately 10% in the 15% cecal contents.
Aspergillus oryzae alpha-amylase hydrolyzed the conjugate to small saccharide conjugates, such as the triose and maltose conjugates, but there was no appreciable release of n-butyric acid. The conjugate was less susceptible to carboxylic esterase (from porcine liver), thus releasing no appreciable amounts of n-butyric acid.
On the other hand, a fast release of n-butyric acid was observed when the esterase was employed after amylase hydrolysis, suggesting that two types of enzymes, sugar-degrading and ester-hydrolyzing enzymes, are necessary for the release of n-butyric acid from the conjugate in large intestinal contents.
Valeric acid chitosan conjugates for drug delivery
The aim of this study was not to target a short chain fatty acid to the colon but rather to target chemotherapy agents to the liver.  Chitosan as a biopolymer was modified using a hydrophobic moiety and valeric acid in order to increase its in vivo stability.  The authors were completely unconcerned with “amidases” to break the valeric acid/chitosan amide bonds.
Monocarboxylate transporters 
MCT1, MCT4, and SMCT1/2 seem to be the main colon short chain fatty acid transporters.  ProteinAtlas.org did not have any information as to whether the Na+ depenent transporters are expressed in the small intestine. MCT1 requires an ancillary protein for its trafficking to and localization in the plasma membrane; CD147, a widely expressed glycoprotein. 
Even short chain fatty acids can be absorbed by passive diffusion in the stomach, they may be predicted acidify the intacellular pH. Perhaps we will need to assume that the TessMed formulation is designed to prevent this from happening.
- Hirayama F, Ogata T, Yano H, Arima H, Udo K, Takano M, Uekama K. (2000) Release characteristics of a short-chain fatty acid, n-butyric acid, from its beta-cyclodextrin ester conjugate in rat biological media. J Pharm Sci. 2000 Nov;89(11):1486-95.
- El-Marakby EM, Hathout RM, Taha I, Mansour S, Mortada ND. (2017) A novel serum-stable liver targeted cytotoxic system using valerate-conjugated chitosan nanoparticles surface decorated with glycyrrhizin. Int J Pharm. 2017 Jun 15;525(1):123-138.
- Sivaprakasam S, Bhutia YD, Yang S, Ganapathy V. Short-Chain Fatty Acid Transporters: Role in Colonic Homeostasis. Compr Physiol. 2017 Dec 12;8(1):299-314.free article