Let's Get Iontophoresis Done. (Knowledge and Data Dump)

[inbrugge]

In our previous thread we were trying to come together to find a proper way of applying CB. The most logical method seemed to be through iontophoresis and other galvanic devices. Luckily, we just got Desmond's great discoveries for CB. So for now, it seems that we have a practical solution for CB.

However, I have belief that we should continue to pursue iontophoresis in general. I believe topical delivery is not just a problem for CB. It is a limitation that is hindering the efficacy of ALL EXISTING TREATMENTS including MINOXIDIL. And, again, I have firm belief that iontophoresis is the best method to surpass this limitation as it directly opens up the scalp's pores and bypasses all the chemistry involved in penetrating the scalp for regular topical vehicles.

IN ADDITION, Iontophoresis devices are FAIRLY offerdable and easily accessible. You can get them off Amazon and eBay for between 200$-1000$. If this machine provided a great advantage in halting hair loss, I'm sure all of us would cough that up.

So let's put together an effort to combine our knowldege and expertise so we can:

1. Learn the ins and outs of iontophoresis. What are the terminologies? what are the differences (hydrophorosis, galvanic devices, etc)?

2. Use this theoretical knowledge on iontophoresis to apply it to actual treatments such as: FINASTERIDE, DUTASTERIDE, MINOXIDIL, MINOXIDIL SULPHATE, CB-03-01, RU, SPRIO, ETC. What would we need to do to apply each topical through the use of iontophoresis? Would this delivery method provide significant advantages? Would it cause any significant downsides (increase in systematic side effects, etc)?

3. Finally, streamline the process of application of these topicals and get together a team of people to try it out and document the process. For example, if we could use iontophoresis to apply CB, we could get a group of 20 people to apply it using our method and document their progress.

So what do you guys say? Anyone interested?

[inbrugge]

I have decided to make a post (which explains in understandable terms) what makes a good vehicle for drug delivery through the skin. I have collated information from several journals which required my institutional login and made a list of component carriers which I feel is important for penetration of CB-03-01 as a compound that has a molecular weight that is nearing Lipinskis rule of 500. I have tried to compile information from which we can readily produce carriers ourselves as we do not have access to materials and methods used by pharmaceutical companies.

A brief explanation of what we are trying to penetrate:

Vehicles designed to enhance drug delivery through the skin must incorporate specific elements that improve the ability of the delivery system to overcome the barrier posed by the stratum corneum.

Structure of the skin: its barrier properties: Human skin is, on average, 0.5 mm thick and is composed of four main layers: the stratum corneum (SC), viable epidermis, dermis and subcutaneous tissue.

Stratum corneum: The thick (10–20 mm) surface layer, the SC, is highly hydrophobic. Because of its highly organized structure, the SC is the major permeability barrier to external materials, and is regarded as the rate-limiting factor in the penetration of therapeutic agents through the skin.

Viable epidermis: The role of the viable epidermis in skin barrier function is mainly related to the intercellular lipid channels and to several partitioning phenomena. Depending on their solubility, drugs can partition from layer to layer after diffusing through the SC.

Dermis and hypodermis: Hair follicles, sebaceous glands and sweat glands are found here and might serve as additional specific, albeit fairly limited, pathways for drug absorption (IONTOPHORESIS). In some cases, for example, hair follicles might act as target sites for drug delivery. This route is via the hair follicles and sebaceous glands and is called the shunt or appendageal route. Iontophoretic drug delivery uses an electrical charge to drive molecules into the skin primarily via the shunt routes as they provide less electrical resistance, and vesicular delivery and this is why COSMO achieved such good results with this device as it reaches the receptor site immediately and directly.

Improvement of drug flux by chemical enhancers: Transdermal drug delivery requires that suitable quantities of drug be transported through the skin using ‘penetration enhancer’ compounds and physical techniques. Penetration enhancers, in general, promote drug diffusion by disturbing the structure of the SC and/or deeper layers.

Solvents: Many harsh solvents and chemicals have been shown experimentally to compromise the epidermal barrier, resulting in enhanced drug delivery however they are not fit for pharmaceutical use. I have found the following mixtures that are unfit: acetone and ether mixtures, chloroform-methanol (2:1) mixture, hexane-methanol (2:3) mixture, acetone/ petroleum ether mixtures and finally 2:1 mixture of chloroform-methanol.

Pharmaceutically acceptable enhancers:

I will present this as the following. The class of the enhancer (bold), followed by representative compounds (italic) and their mechanism of interaction with skin and enhancement of drug permeability:

Water:

Hydrating and occlusive (meaning air and water tight) topical preparations- Hydrates the SC, evidence for increasing permeability of both hydrophilic and lipophilic compounds, increases fluidity or disorder of intercellular bilayers.

Occlusive dressings (meaning air and water tight)- occlusive dressings and vehicles prevent water loss from skin and provide full hydration

Organic solvents:

Alcohols (ethanol) – co -transports with the drug through the lipid channels, partial extraction of lipids

Polyols (PG) - replaces bound water in the intercellular space, enhances penetration of lipophilic drugs

Sulfoxides (DMSO) – increases lipid fluidity and disrupts lipid packing

Pyrrolidones - interacts with both the keratin and lipid component of the SC

Fatty acids:

Oleic acid etc - Increases fluidity of the intercellular lipids: shorter chain (C10–12) and branched or unsaturated chain fatty acids are more effective than longer chain saturated fatty acids; the vehicle used (e.g. PG) might be synergistic.

Terpenes:

Ascaridole, 1,8-Cineol, Menthol etc - Disrupts intercellular lipid order; increases electrical conductivity, indicates the opening of polar pathways in SC.

Surfactants:

Polysorbates etc - Penetrates into skin, micellar solubilization of SC lipid

Azone:

Thiazone etc - Disrupts skin lipids in both the head group and tail region

Phosphollipids (liposomes) [More on this in another post)

From the above you can see why PG/OL is one theoretically viable combination and why it is spoken of often. Also you now know the different class of enhancers which could improve delivery. A suitable vehicle is going to emerge that has a combination of the above in differing compositions and concentrations. I have tried to use representative compounds that are commercially avaible to some extent however other similar compounds that are more commercially availible can also be used.

Some reading for us on stuff that user adam k compiled on another thread.

[inbrugge]

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.

more reading compiled by adam k.

[inbrugge]

List of Articles Regarding the Use of Iontophoresis for Topical Delivery.


General Info on Iontophoresis

http://www.electrotherapy.org/modality/iontophoresis

Iontophoresis, Applying Minoxidil to Scalp, Direct Current

http://www.google.com/patents/US5195953

Method for Stimulating Hair Growth with Cationic Derivative of Minoxidil Using Therapeutic Iontophoresis
http://www.google.com/patents/US5466695

http://www.google.com/patents/US5466695

Iontophoresis-Targeted, Follicular Delivery of Minoxidil Sulfate for the Treatment of Alopecia.
http://www.ncbi.nlm.nih.gov/pubmed/23450524

Iontophoretic Transdermal Delivery of Finasteride in Vesicular Invasomal Carriers

http://www.eurekaselect.com/107745/article

Development of a Portable Iontophoretic Drug Delivery Device with In-Vitro Experiments for Androgeneticalopecia Treatment

http://pjms.com.pk/index.php/pjms/ar...wFile/1684/406

Topical Delivery of Active Principles: The Field of Dermatological Research

https://escholarship.org/uc/item/9sh763nc

Design and Implementation of Iontophoresis Multiple Flexible Sensors for Treatment of Hair Loss

http://link.springer.com/chapter/10....76-0_66#page-1

The Use of Acetic Acid Iontophoresis in the Management of a Soft Tissue Injury

http://www.ncbi.nlm.nih.gov/pmc/arti...MC3096143/#B15

Iontophoresis: Applications in Transdermal Medication Delivery

http://physther.net/content/75/6/554.full.pdf

Transdermal Administration of Anti-Inflammatory Medications in Sports Injuries: Use of Iontophoresis and Phonophoresis to Enhance Delivery

http://www.thehealthychoice.net/PDF/IJPCTransdermal.pdf

Enhanced Transfollicular Delivery of Adriamycin with a Liposome and Iontophoresis.

http://www.ncbi.nlm.nih.gov/pubmed/15009101

Cosmo Reports Exciting Results in P.O.C. Alopecia Study

http://www.cosmopharmaceuticals.com/...010-10-06.aspx

Vitamin C Iontophoresis

http://stamfordskin.com/en/treatment...horesis-2.html

[inbrugge]

Is no one interested in this? I can't be the only one?

[Suicide]

Definitely interested, but not at all interested in being among the first to experiment :/

[xHELLSEHERx]

Good work! Thanks a lot.

[Kudu]

Is no one interested in this? I can't be the only one?

Hey man, I haven't forgotten by any means, it's just that I'm busy as hell and I've put it on the back burner for a while.

Guys, unless you buy a machine that is over a thousand dollars, this isn't dangerous. The worst thing you can really do is blister yourself slightly, and that's only possible if you leave the diode on your head for 30 minutes without anything to alter the current going into your skin. Put a water based gel on your head, apply a charged ingredient, then run the diode over the applied area for 15 minutes. If your average spa chick can do it, so can you. You aren't going to push a chemical through your body and cause damage with a $300 device, it is not strong enough.

There is a ton of youtube videos on this, people buy these things and use them at home for aging treatments all the time. It's not exactly simple, but it's not rocket science.

Now, the easiest thing we can do to right now to apply this technology would be to use it with Minoxidil Sulfate, there is a decent study showing how it improved minox results substantially, while only having to apply it every three days. Personally I would love to use Bimatoprost with iontophoresis but I haven't looked into it yet, it may not work. Nevertheless, the previously stated would work and probably quite well. I'll look into it again, it's been a shitty day so might as well lol.

[burtandernie]

So CB is chemically neutral and you have to give it a charge to electrically propel it so the chemical has to have a charge positive or negative. How are you going to do that? Just sounds way too hard, dangerous, and time consuming for me but good luck

[Kudu]

Screw CB, it'll either work or it won't with Versapro. RU would probably be great with iontophoresis but, again, it's not charged. There are ways to add to the molecule so that it becomes charged, to make it simple, it works like magnets in a way. The problem is, no one offers the modified drugs so that they could be used, and I'm sure they would be expensive if they did. Hard? Possibly. Dangerous? Nah. Time consuming? Yes. Expensive? Without a doubt.

This can be used, if you can deal with all of the above, it would be the initial investment and learning that would be difficult. After that, you would probably get very good results with multiple treatments, while using smaller amounts and applying only a couple of times a week. I don't blame you though, I don't have the time right now that's for sure.