Discussion on the "Highly soluble formulations of harmine" patent

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This thread is to discuss the patent "Highly soluble formulations of harmine": WO2024023274A2 - Highly soluble formulations of harmine - Google Patents

I'll quote the already existing posts here:

It was an objective technical problem of the present invention to provide a formulation of harmine characterized by its improved solubility. The objective technical problem is solved by embodiments disclosed herein and as characterized in the claims. The present inventors have surprisingly found that compositions comprising harmine (or a pharmaceutically acceptable salt thereof) and (i) an uronic acid or (ii) a carboxylic acid and a monosaccharide are characterized by significantly improved solubility than the state of the art formulations of harmine, including harmine free base or harmine hydrochloride (see e.g. Table 12 and Table 14). Said compositions show better bioavailability and less subject-to-subject variability in comparison to state of the art composition.

I skimmed through a few spots and tables in that patent. That's quite interesting indeed. Thanks for the link.

Seems like D-glucuronolactone would be easy and cheap to source which appears there are some resources outlining the degradation of D-glucuronolactone into D-glucuronic acid and vice versa. Though I've not had enough time to try and source the full paper from the vast dark / clear web if it can be located.

Reading about it, I don't know if it's very amenable to kitchen chemistry. It looks like it would be quite difficult to get a good yield and avoid subproducts.

But there's the other option:




So malic acid and glucose, sounds pretty easy! It's worth a try.

So dissolve freebase harmalas with distilled white vinegar and sweeten with table sugar. Or am I missing something?

According to the patent: the molar ratio of harmine to acid needs to be between 0.5:1 and 2:1, preferably 1:1. The molar ratio of acid to monosaccharide has to be in the same range with the same preference. So it should be roughly a 1:1:1 ratio in moles. So for 1g harmalas, roughly 300mg acetic acid or 600mg malic acid, and 900mg glucose.

This estimation is with harmala freebase in mind and it would have to be with harmala salts, but I don't really know how to know the molar mass of the salt. @Transform, is it as simple as assuming one molecule of acid per molecule of harmine or harmaline?
As there is a wide margin for the ratios, it shouldn't matter too much.

It calls for a monosaccharide and table sugar (sucrose) is a disaccharide. So it's better to use pure glucose or fructose.

I was wrong, it's with the freebase:


They then later claim the salt as well, but it being a patent it's hard to know if it works or they claim it just to claim as much as possible.

The main contribution of the patent seems to be that harmine glucoronate is extremely soluble when compared to other salts. I wonder if many of the other claims may just be to make the patent as broad as possible. But as the formulation with an acid and a monosaccharide is so simple, I think it's worth a try.

It would be good if more knowledgeable people than I take a look at it. My lack of knowledge of chemistry plus the extremely verbose and repetitive language make it very hard to understand for me.

 

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Harmine vs Harmaline vs Mixed Harmalas

What dose have you both settled into out of curiosity with harmalas and or individually? I've always taken them unseparated and I just take whatever feels right at the moment. For pharmahuasca I would take 200+ mg freebase. Recently I've been taking around 100 mg daily in the morning for mood...

forum.dmt-nexus.me

Ultimately it should be the salt right? Isn't that what the acid is for to salt the freebase?

I'm really not sure. They explicitly test the solubility of the salts and find them to not be good. Then they claim that in this formulation, either harmine or a "pharmaceutically acceptable salt" can be used.

They also don't explain or hypothesize why this formulation may be more soluble.

 

[Sakkadelic]

I'm tempted to try honey, unlike sugar it's supposed to be a mixture of glucose and fructose as monosaccharides. I don't have a pure monosaccharide on hand. The ratios they provide in the patent seem forgiving

 

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I'm tempted to try honey, unlike sugar it's supposed to be a mixture of glucose and fructose as monosaccharides. I don't have a pure monosaccharide on hand. The ratios they provide in the patent seem forgiving

A kind of gross alternative that would likely work is to dissolve sugar in saliva. Its enzymes should break down sugar into glucose and fructose. As the amount of monosaccharides needed is low, it could work well. But it's somewhat disgusting haha.

 

[Sakkadelic]

Patents tend to use fancy terms and convoluted ways to explain simple details. I will read it it in full later but it doesn't sound like a sensetive reaction is happening where conditions need to be precise. It's worth trying simple home techniques

 

[Transform]

I was wrong, it's with the freebase:


They then later claim the salt as well, but it being a patent it's hard to know if it works or they claim it just to claim as much as possible.

Probably the latter, and it's so simple that it counts as prior art, making the patent invalid. We know that sweet harmala brews are active. Shall we patent the idea of mixing a harmala salt with honey, then?

They also don't explain or hypothesize why this formulation may be more soluble.

That's because it's a catch-all patent and not a scientific paper, but an attempted 'intellectual property' grab.

Be sure to formulate your commercial harmala preparations with a molar ratio of 0.498 or 0.202, just to be on the safe side

 

[blig-blug]

That's because it's a catch-all patent and not a scientific paper, but an attempted 'intellectual property' grab.

It's very likely, yes. Still, it's so easy that it's worth a try following it as they suggest it.

However, their finding that harmine glucuronate is much more soluble seems to be genuinely new information. They say harmine HCl has a solubility in water of about 25mg/ml while harmine glucuronate has 406mg/ml. That would mean it's much easier to absorb sublingually. I think this is interesting, unless it was already well known information.

Unfortunately, glucuronic acid doesn't seem easy to find.

 

[Transform]

Glucuronic acid - Wikipedia

en.m.wikipedia.org

Natural sources are available, including urine, apparently.

 

[Sakkadelic]

They say harmine HCl has a solubility in water of about 25mg/ml while harmine glucuronate has 406mg/ml.

Bringing this qoute here too

A composition comprising harmine, fructose and malic acid in a molar ratio of 1 :0.5:0.5 was dissolved to 21 % in water by combining 212 mg harmine FB, 90 mg fructose, 67 mg malic acid and 1.0 g water. A transparent solution has been obtained.

Yeah it does seem a concentration of ~200 mg/ml harmala is pretty good. 0.1 ml for a 20 mg sublingual dose sounds very appealing.
But then how to dissolve it in the first place in so little water if it's not already in the highly soluble form?

 

[blig-blug]

But then how to dissolve it in the first place in so little water if it's not already in the highly soluble form?

Nothing about this is too clear. I'm guessing an option is to dissolve it at the same time, or to dissolve it in more volume and evaporate the water first. I do suspect that it has to be with freebase, the point of the acid is just form the salt (hence the preferred 1:1 molar ratio), and any actual difference is due to the glucose or fructose. So maybe one can just add the glucose first and the harmala salts afterwards.

 

[Transform]

[Notice the molar ratio (0.5) for malic acid takes into account its dibasic properties.]

But then how to dissolve it in the first place in so little water if it's not already in the highly soluble form?

Adding water to the mixture with that stoichiometry will cause it to dissolve by continuous reaction of the acid and the harmine FB until one or the other (hopefully both) gets used up, or the solubility limit is reached, in which case more water can be added. The fructose will also be dissolving, and presumably enhancing the solubility of the salt as the latter forms.

 

[Sakkadelic]

It's maybe also possible to add the harmala freebase slowly to the sweet&sour solution.

I actually did make a crude attempt earlier with 25 mg mixed harmalas freebase, 250 mg 5% acetic acid, and 100 mg honey. Nothing important to report and it's unlikely that it worked as intended in the patent. it didn't taste like much under my tongue but later when I swallowed it, it was still quite bitter. And I had a long drive after so I didn't focus on the subtle effects.

I will try it soon again with further purified harmalas and more appropriate ingredients.

 

[DetritusTheEgo]

Glad that where my mind was at yesterday when I replied came to fruition. When I replied I thought this should probably get forked into its own thread and also thought how can combining a few acids with harmine freebase in water warrant a patent. I guess they do some sublingual disintegrating tablets but I'm guessing that also isn't novel Calcium Phosphate Microcapsules as Multifunctional Drug Delivery Devices. The patent topic seems to have been mentioned so glad I wasn't off base.

Reading about it, I don't know if it's very amenable to kitchen chemistry. It looks like it would be quite difficult to get a good yield and avoid subproducts.

Curious what reading you had located regarding the conversion / byproducts for some additional reading on my part. I'll look a tad more later either way. After the discussion early on in Harmine vs Harmaline vs Mixed Harmalas between Transform and Sakkadelic about AI

The same caveat applies as with all other groups of specialist information - the outputs from a machine learning chatbot require a reasonably advanced level of knowledge in the field in order to sensibly interpret and above all verify them.

I wasn't trusting what it was stating that D-glucuronolactone and D-glucuronic acid are in equilibrium with one another in the solution and could swing the equilibrium via pH to D-glucuronic acid when basic and D-glucuronolactone when acidic. It was stating you could convert nearly all D-glucuronolactone into D-glucuronic acid with a pH of 8-10 plus heat and time. Then acidify it down to 3-4 pH with citric acid and evap the liquid off. Acidifying likely would result in some conversion back into D-glucuronolactone which had indicated expect a 70-90% D-glucuronic acid conversion. That or use it as is in solution and adjust pH. I still need to read fully through the Degradation Kinetics of Glucuronic Acid in Subcritical Water you graciously attached which uses subcritical water as well as the full patent. I'm in the boat where I can grasp the topics on a surface level but fail to understand the underlying mechanisms and the why.

From the patent text I found it weird the formulation F4 with harmine glucoronate was administered to dogs with DMT whereas every other formulation they did on humans and didn't administer with DMT. Looks like the F4 formulation had a high "harmine to harmol ratio is approximately 50:1 (250ng/ml : 5ng/ml)" blood plasma level but they also stated "in experiment C, a much higher harmine doses were administered (8 vs. 1.3 mg/kg BW), which may have led to the saturation of harmine degrading enzyme systems and thus a disproportional increase of harmine levels compared to its metabolite harmol." They didn't test F7 harmine glucoronate sublinqual tablet + DMT but mention of an upcoming planned study which the patent was in 2023.

Looks like Reconnect Labs Ag went on to do a couple more studies released this year with something equivalent to the F6 formulation which was Harmine HCL + DMT in a fast disintegrating sublingual tablet Examining the pharmacokinetic and pharmacodynamic interaction of N,N-dimethyltryptamine and harmine in healthy volunteers: Α factorial dose-escalation study and Population pharmacokinetic-pharmacodynamic modeling of co-administered N,N-dimethyltryptamine and harmine in healthy subjects but couldn't find the use of the F7 formulation using harmine glucuronate sublingual tablets.

All that said, making a sublingual liquid regardless of it's bitterness sounds quite obtainable and interested to look at the fructose / malic version and others potentially that Sakkadelic quoted earlier.

 

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Curious what reading you had located regarding the conversion / byproducts for some additional reading on my part

Nowhere new, just the paper you found.

More noteworthy is the uneven material balances between GlcA and GlcL, which implies the presence of other degradation products.

Despite the small amounts of GlcA produced during the degradation of GlcL, GlcA demonstrated a strong effect upon pH. The degradation of GlcA resulted in a comparably less significant rise in pH. Even at the highest recorded consumption, the pH value showed only a modest increase, of approximately 0.3. With a pKa value of about 2.9, GlcA is a weak acid with a small extent of dissociation. Therefore, the observed pH changes are likely to be attributed to the comprehensive effects of other factors, including the other degradation products, although no further investigation was done

So, if I understand that correctly, it means that the degradation of glucuronolactone into glucuronic acid produces only small amounts of glucuronic acid, and potentially degradation products.

From the patent text I found it weird the formulation F4 with harmine glucoronate was administered to dogs with DMT whereas every other formulation they did on humans and didn't administer with DMT

Yes, that caught my eye too. I wonder if it being a new salt, they weren't allowed to test it directly on humans. It seems they stumbled upon the glucuronate while looking for ways of making harmine easier to absorb, but couldn't use it.

By the way, look at this absolute joke: https://reconnect-labs.com/wp-conte...abs_Integrity_Statement_and_Patent_Pledge.pdf
They oh so generously "pledge" to not sue any Indigenous communities using Ayahuasca in a traditional context. Are they implicitly admitting their patent to be so overly broad that it potentially covers previous art from millennia ago?
Also, looking at different patents (in general, not only theirs), there are basically infinite variations of "all forms of DMT and harmalas/MAOI". I knew there were some overly broad or bogus patterns. But it seems to be the norm, not just some cases.

All that said, making a sublingual liquid regardless of it's bitterness sounds quite obtainable and interested to look at the fructose / malic version and others potentially that Sakkadelic quoted earlier.

In about a week I'll have access to malic acid and fructose, so I'll try it too. If it really makes it possible to dissolve 200mg in a single ml it would be good.

 

[Transform]

seems they stumbled upon the glucuronate while looking for ways of making harmine easier to absorb, but couldn't use it.

I seem to recall having suggested trying glucoronic acid in formulating harmala e-juice some months ago, in a conversation with @_Trip_, so these guys may actually be directly ripping off our ideas. Thanks. Make sure you donate generously to the Nexus, @reconnect-labs…

Lazy alkaloid salting combos (CISLO)

I wouldn't know anything about 4-hydroxybutanoate or where to get it. I can tell you lactate was the worst to work with and yeilded very little, malic and tartaric worked well. My preference would be tartaric as it reacted far better than malic but malic could be decanted. I will still need to...

forum.dmt-nexus.me

The polyol acids are considered safe for use as food additives - I think their hydrophilic nature will make them safe for inhalation but it's never 100% guaranteed. But the closely-related glucuronic acid is an essential component of human metabolism. The body will have no trouble dealing with gluconic or saccharic acid at usual vaping amounts.

Glucono delta-lactone - Wikipedia - gluconic acid is formed directly from this safe food additive by hydrolysis, and 'effortlessly' metabolised by the body.

https://www.sigmaaldrich.com/US/en/product/sigma/s4140

"D-Saccharic acid potassium salt is present in plants and animals. It is produced by the chemical oxidation of glucose with nitric acid. D-Saccharic acid lowers cholesterol and has chemotherapeutic property. It also has antimutagenic activity."

 

[_Trip_]

I seem to recall having suggested trying glucoronic acid in formulating harmala e-juice some months ago, in a conversation with @_Trip_, so these guys may actually be directly ripping off our ideas.

Its all me Transform! That's right I took your idea and got a patent now time to profit!!!!

 

[Transform]

Its all me Transform! That's right I took your idea and got a patent now time to profit!!!!

Well, I guess it helps pay the bills, and if it was going to be anyone, I'd be happy for you, @Loveall and @endlessness to benefit from this

 

[_Trip_]

If only. But looks like we need to look into your idea glucoronic acid

 

[doubledog]

Quite weird, what is the reason for this? Sublingual route is quite effective even with a freebase, I assume that some form of sublingual tablets can be easily prepared.
Is the main goal to prepare some kind of sublingual spray?

 

[blig-blug]

Sublingual route is quite effective even with a freebase

According to the measurements referenced in the patent, not that much. It seems absorption is not fast enough so you end up swallowing part of it.
I don't know what to think. I do get effects from sublingual, but never as strong as oral. For example, I don't think you can get a single sublingual dose to have the effect 300mg harmalas will have. Would you agree, in your experience?