(CB-03-01 Vehicle Research) PhD Student in Chemistry

[Westonci]

This is probably going to sound really dumb (i have no scientific background).

I was wondering could we use dermarolling as a way to deliver the Cb-03-01 without having to use any creams or what not.

[chimera]

This is probably going to sound really dumb (i have no scientific background).

I was wondering could we use dermarolling as a way to deliver the Cb-03-01 without having to use any creams or what not.

No, you can't. Because CB comes in powder form.

[mari0s]

From what I see the transdermal steroid carrier seems okay and viable. The carrier is a long chain alcohol which is good for hydrophobic molecules and CB is log P 3.73 which is quite hydrophobic.

Hi i don't know if could be useful but from were i live it's been often used in topical lotions made by pharmacies with good results a similar steroid: cyproterone acetate and the veichle used is transcutol at 5% + alchol 85°

[adam k]

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.

[adam k]

Great stuff Adam!

One nagging question though; can CB in any way affect libido? And, given that its a steroid, what would its potential be to cause skin atrophy when applied at 10mg per 1ml once a day? Any concerns?

Thanks bro. CB shouldn't affect libido as it is applied topically and is an androgen antagonist. From what I gather the beauty of this compound is that it metabolises to an inactive form when it detaches from the receptor. This is just from what I have seen from some reading, I don't know anything more about this, as its not my area of expertise. Similarly I couldn't answer whether it would cause skin atrophy over long term usage as I'm a pure chemist. However it has been used in trials by Cosmo and passed safety phases right?

[PatientlyWaiting]

No, you can't. Because CB comes in powder form.

So how do we use CB on our heads if its a powder? Do we eat it with fried chicken, or mix it with Gatorade and drink it?

[tmw]

so Adam, is plain words, what can be idea for a proper vehicle? why do you consider the acetone unfit? In EU many topicals are made with acetone and PPG with pretty good results

[chimera]

So how do we use CB on our heads if its a powder? Do we eat it with fried chicken, or mix it with Gatorade and drink it?

No genius. You mix the powder with a compound which serves as a vehicle, which one? we don't know yet, that's what people in this thread is tring to find.

[Westonci]

No, you can't. Because CB comes in powder form.

Sorry another stupid question.

So what would happen if you just put the powder on your head, after dermarolling.

Wouldnt the powder make its way into or near the hair follicle if you used a 1.5 -2 mm dermaroller.

[hellouser]

Sorry another stupid question.

So what would happen if you just put the powder on your head, after dermarolling.

Wouldnt the powder make its way into or near the hair follicle if you used a 1.5 -2 mm dermaroller.

Nothing, it would just sit there. It needs to break down and dissolve into a molecule lighter than 500 dalton as thats typically the most skin will allow. Dermarolling/wounding should (and likely does) allow much better penetration with heavier molecules however raw powder isnt going to do anything for you.

Not sure why youre asking about this though, it almost seems as if you want to skip the whole ethanol/pg or oleyl/pg vehicle, its absolutely vital. The only way you'd be able to skirt around this is through injections (mesogun/diabetic needle) or iontophoresis.

[rdawg]

sooo couldnt we just simply get CB, mix it with each of the vehicles that adam listed above and see/test which one gives it a molecular weight under 500?

Isn't there a way to measure that?

or am I missing something here?

[chimera]

We could end up using a vehicle which affects the CB composition, rendering it useless, we don't want that to happen.

CB is not so cheap you know?, trying in every vehicle would take much money, which I'm sure not many around here are willing to risk.

Even worse, trying every vehicle would take a lot of time.

[adam k]

sooo couldnt we just simply get CB, mix it with each of the vehicles that adam listed above and see/test which one gives it a molecular weight under 500?

Isn't there a way to measure that?

or am I missing something here?

It is not like that at all. The molecular weight of CB remains the same (402) regardless what vehicle it is in. We are looking for 2 factors for a successfull vehicle system: 1) solubility 2) penetration.

We could end up using a vehicle which affects the CB composition, rendering it useless, we don't want that to happen.

CB is not so cheap you know?, trying in every vehicle would take much money, which I'm sure not many around here are willing to risk.

Even worse, trying every vehicle would take a lot of time.

I know bro but we have not got access to tests such as these:

http://www.cyprotex.com/transdermalpermeability/

I have spent all day today doing computer simulations on skin permeability but software like this is not commercially availible not to mention extremely niche and the one I have managed to use it pretty crude and it will only let me run one vehicle at a time. Even that is producing some errors which is driving me nuts. I can say with a degree of certainty that multi component simulation testing of vehicles CAN NOT be done by even the most advanced amongst us. Trials are the only way.

This is not as bad as it sounds because PG/OL is quite promising in itself. Then gradually more components can be added like DMSO or fatty acids which shouldn't render it useless but only increase efficacy.

It's pissing me off because pharmaceutical companies have all kinds of in vitro tests that would be able to determine a perfect vehicle. They could work it out real quick. We are working with our hands tied behind our backs.

[chimera]

Adam K, my last post was not against you, I was replying to rdawg.

I mean, I know you're trying hard to help us all and I'm very thankful for that.

[adam k]

Adam K, my last post was not against you, I was replying to rdawg.

I mean, I know you're trying hard to help us all and I'm very thankful for that.

Oh I was just reponding to your message because it had some very valid points bro. Sorry I don't know if it came across the wrong way I meant that I'm pissed with the situation as COSMO can do all of this and testing and trials in an accelerated time frame but they are taking their sweet time.