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Iontophoresis delivers a medicine or other chemical through the skin. It propels high concentrations of a charged substance, transdermally by repulsive electromotive force, through the skin. A small electric current is applied to an iontophoretic chamber placed on the skin, containing a charged active agent and its solvent vehicle. Another chamber or a skin electrode carries the return current. A chamber are filled with a solution containing an active ingredient and its solvent vehicle. The positively charged chamber, called the cathode, will repel a positively charged chemical species, whereas the negatively charged chamber, called the anode, will repel a negatively charged species into the skin. Hence if our compound is positively charged we place it in the cathode and if it’s negatively charges we place it in the anode.
The problem faced by us is that CB 03 01 is chemically neutral. Most steroids are chemically neutral molecules at physiological pH though it is sometimes possible to chemically modify them in order to form prodrugs containing an acidic group (e.g., sulphate or phosphate) that are negatively charged in physiological conditions. Once the produg passes the skin it is hydrolysed back to its original active form. For example, dexamethasone phosphate is a prodrug of dexamethasone and is doubly charged at physiological pH. Iontophoresis from the cathode is therefore expected to increase the delivery of these anionic prodrugs.
My theory is that Cosmo used a phosphating/or sulphating agent to add a phosphate/or a sulphate ester to the alcohol functional group on carbon-21. Below is the scheme:
In a previous post I was confused as to how Iontophoresis could achieve such few applications whereas the topical would require once/twice daily applications. This was also echoed by a few people and I’m guessing the following. As a prodrug needs to be hydrolysed twice to reach the inactive cortexolone form (1st hydrolysis = active form CB, second hydrolysis = inactive form Cortexolone) this would be able to stay in the skin for longer. Another guess is that Cosmo used a phosphating reagent that had a bulky group which would cause steric hindrance to the phosphate ester, thereby slowing the rate of hydrolysis even more and keeping the prodrug in the skin for longer.
Now the problem with this is that is an extremely tricky reaction, with all kinds of sh*t that can happen and all kinds of side reactions and pathways can occur. This type of reaction can only be done under controlled conditions in a lab with other reagents to help facilitate the process. It is not something that we could do ourselves. But this is just the first step of the problem. Let’s just say we were to obtain the pro drug form. It is not a simple case of just wacking it into a vehicle and then using Iontophoresis.
The following is just to show you how complex it would be. It would need to be prepared in deionized water at a specific pH. To avoid the inclusion of unwanted anions inevitable when a strong acid is used to lower the pH, an equimolar mixture of the diacid and its conjugate base would need to be dissolved in water to obtain a final conc. of CB-03-01-Phos. CB-03-01-H2-Phos would have to be prepared from the disodium salt by adding HCl to a solution of CB-03-01-Na2-Phos in water. The insoluble dihydrogen acid would precipitate and would need to be recovered by liquid extraction, leaving a powder of CB-03-01-H2-Phos which contains only trace amounts of unwanted ions.
Then to carry out Iontophoresis, a specific procedure would have to be carried out by mixing phosphate-buffered saline, sodium, potassium, chloride and phosphate at a certain pH.
As you can see, the above processes are complex, tedious and require lots of reagents and special techniques. Also ionto requires using sticky electrodes on the skin. I don't see how this could be attached to the scalp unless somebody was slick bald. That is another problem. Therefore based on my current research, my view is that using Iontophoresis ourselves is not viable.
The problem faced by us is that CB 03 01 is chemically neutral. Most steroids are chemically neutral molecules at physiological pH though it is sometimes possible to chemically modify them in order to form prodrugs containing an acidic group (e.g., sulphate or phosphate) that are negatively charged in physiological conditions. Once the produg passes the skin it is hydrolysed back to its original active form. For example, dexamethasone phosphate is a prodrug of dexamethasone and is doubly charged at physiological pH. Iontophoresis from the cathode is therefore expected to increase the delivery of these anionic prodrugs.
My theory is that Cosmo used a phosphating/or sulphating agent to add a phosphate/or a sulphate ester to the alcohol functional group on carbon-21. Below is the scheme:
In a previous post I was confused as to how Iontophoresis could achieve such few applications whereas the topical would require once/twice daily applications. This was also echoed by a few people and I’m guessing the following. As a prodrug needs to be hydrolysed twice to reach the inactive cortexolone form (1st hydrolysis = active form CB, second hydrolysis = inactive form Cortexolone) this would be able to stay in the skin for longer. Another guess is that Cosmo used a phosphating reagent that had a bulky group which would cause steric hindrance to the phosphate ester, thereby slowing the rate of hydrolysis even more and keeping the prodrug in the skin for longer.
Now the problem with this is that is an extremely tricky reaction, with all kinds of sh*t that can happen and all kinds of side reactions and pathways can occur. This type of reaction can only be done under controlled conditions in a lab with other reagents to help facilitate the process. It is not something that we could do ourselves. But this is just the first step of the problem. Let’s just say we were to obtain the pro drug form. It is not a simple case of just wacking it into a vehicle and then using Iontophoresis.
The following is just to show you how complex it would be. It would need to be prepared in deionized water at a specific pH. To avoid the inclusion of unwanted anions inevitable when a strong acid is used to lower the pH, an equimolar mixture of the diacid and its conjugate base would need to be dissolved in water to obtain a final conc. of CB-03-01-Phos. CB-03-01-H2-Phos would have to be prepared from the disodium salt by adding HCl to a solution of CB-03-01-Na2-Phos in water. The insoluble dihydrogen acid would precipitate and would need to be recovered by liquid extraction, leaving a powder of CB-03-01-H2-Phos which contains only trace amounts of unwanted ions.
Then to carry out Iontophoresis, a specific procedure would have to be carried out by mixing phosphate-buffered saline, sodium, potassium, chloride and phosphate at a certain pH.
As you can see, the above processes are complex, tedious and require lots of reagents and special techniques. Also ionto requires using sticky electrodes on the skin. I don't see how this could be attached to the scalp unless somebody was slick bald. That is another problem. Therefore based on my current research, my view is that using Iontophoresis ourselves is not viable.
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