Usefullness and stability vitamin B12 in creams

DoreenDoreen Member
edited May 26 in Formulating
I would like to try to formulate a cream with vitamin B12 as topical active (eczema).
Vitamin B12 is an effective scavenger of nitric oxide. NO has been found to be implicated in the pathogenesis of (atopic) eczema and psoriasis.
I've found a research showing that the experimental application of a NO synthase inhibitor (N omega-nitro-L-arginine), led to a clear decrease in pruritus and erythema in atopic dermatitis, so one would expect a comparable effect from vitamin B12.

Point is which form?
Some researches (the excerpts) don't mention the form of B12 used.
Some use cyanocobalamine. I also found a simple W/O emulsion formula with it:
·         0.07 g vitamin B12 (cyanocobalamin)
·         46 g avocado oil
·         45.42 g water
·         8 g methyl glucose sesquistearate
·         0.26 g calcium sorbate
·         0.25 g citric acid

The form I can get hold of is hydroxocobalamine. Cyanocobalamine as well as OH-cobalamine are two biologically inactive forms of B12 and need to be converted via a methylation cycle to be fully functional systemically.
Apparently the conversion doesn't seem to be necessary to inhibit nitric oxide though, as OH-cobalamine binds and scavenges NO (source).

My questions:
Since information on topical B12 emulsions (especially with OH-cobalamine) is very scarce, I really hope people here can help me:

·Does anyone know how stable OH-cobalamine is in an emulsion? 

·What pH range is necessary for it to remain stable?

·Is a buffer recommended?

·Important interactions (e.g. preservatives)?

·Recommended concentration?

·W/O rather than O/W?

I know what I'm planning to formulate would be OTC rather than cosmetic, since I hope it will relieve eczemic laesions. I'm not planning to sell, I will be making it for a family member.
Hopefully it can be succesfully used next to indifferent creams and topical corticosteroids.

Edit: adjusted lay-out

Comments

  • PharmaPharma Member, Pharmacist
    edited May 27
    There's a product line out there, called Mavena B12.
    They originally tried to launch a pharmaceutical product for the Swiss market but were turned down by authorities (it was likely lobbying or some bureaucratic A-hole who didn't like the idea of a cost-efficient vitamin cream helping sick people, don't recall what exactly it was but it was some lame, bogus excuse). Hence, they started their business without the intended health claims in Germany and once established there could also sell in Switzerland (as a cosmetic product, not an OTC "drug").
    Innovative, nice product line-up, great results, probably not the soundest scientific foundation (not bad either, lower budgets have that side effect...). What'cha want more?
  • DoreenDoreen Member
    @Pharma
    Thanks for your reply.
    I didn't know that brand, thanks for mentioning.

    Hopefully I can get some answers to my questions. :)
  • DoreenDoreen Member
    Am I really the first here to ask about topical vitamin B12? 🤔
    Hopefully not the last.
  • PerryPerry Administrator, Professional Chemist
    I don't know the answers to your questions and it's unlikely that anyone here will. Vitamin B12 isn't an ingredient commonly put in skin products.

    I didn't find any pH range information in this study which is the full paper of the study you are probably reading about. https://www.dropbox.com/s/waf7hg5c4br2rid/vitaminb12-study.pdf?dl=0

    But you should clarify some of your questions.

    1.  ·Does anyone know how stable OH-cobalamine is in an emulsion? 
    What do you mean when you say "stable"? What measurement would be taken to indicate to you that the ingredient is stable? If you are suggesting that "stable" means that "it still works over time" this answer is unknown. That would be a research study that hasn't been done.

    2. ·What pH range is necessary for it to remain stable? 
    see question 1.

    3.  ·Is a buffer recommended?
    I don't know. I don't think anyone knows.

    4. ·Important interactions (e.g. preservatives)? 
    I know cyanocobalabin can make a product turn pink at low levels.

    5. ·Recommended concentration?
    The study used 0.07% and said research suggested higher levels had no greater effect.  That's a place to start.


  • PharmaPharma Member, Pharmacist
    Cyanocobalamine solution for injections are buffered although I don't know the pH. Likely, the buffer is used for stability reasons and not to make the injection more comfortable since it's one of the more painful injections and hence often combined with lidocaine.
    According to MSDS, hydroxocobalamine is a stable compound, only contact with other heavy metals (than cobalt) and oxidising chemicals as well as light exposure have to be avoided. But information regarding this particular B12 derivative is incomplete. Cyanocobalamine has been better studied: mostly because of the cyano-complex, it is susceptible to light, temperature, air, humidity/water, bases, and strong oxidating agents. It's pH in solution is about 6 which, as a rule of thumbs, is often the most stable pH. According to Wikipedia, it's most stable between pH 4 and 6 and B12 solutions are said to be fairly susceptible to antioxidants such as ascorbic acid.
  • DoreenDoreen Member
    @Perry @Pharma
    I didn't see your replies yesterday, didn't get a notification.
    I will read both of your replies thoroughly and respond later, thanks very, very  much!! :)
  • We formulate  vitamin B12 syrup. pH range is around-5.
    overages added 50% to 100%.


  • SibechSibech Member, Professional Chemist
    @Doreen While it is only done in vitro, B12 worsened the pathogenic factors for acne patients, as the pathogenic strains produce a significantly higher amount of Porphyrins, of which B12 is basically giving them a shortcut. The porphyrins when excited (by UV) cause oxidative damage and allow for growing space in the pore.

    Now I have no clue if topical application of cobalamines would cause any worsening in vivo (I've found no studies indicating anything here), but I thought you might want to know anyway!


    https://msphere.asm.org/content/msph/1/1/e00023-15.full.pdf


    Dabbling Formulator — Qualified Cosmetic Safety Assessor — experienced in claim substantiation & EU regulatory affairs.
  • SibechSibech Member, Professional Chemist
    As for your question on buffer and pH, this might be useful even if it was for an injectable solution. a pH of 4.3 and an acetate buffer was used with the highest level of succes.
    https://jpharmsci.org/article/S0022-3549(15)34243-X/pdf

    Incompatibilities may include ascorbic acid. http://europepmc.org/articles/pmc4179674
    Dabbling Formulator — Qualified Cosmetic Safety Assessor — experienced in claim substantiation & EU regulatory affairs.
  • chemicalmattchemicalmatt Member, Professional Chemist
    For topical use, there should be no need to buffer if your pH is in the normal skin-care range of 3.5 - 6.5. Also, you don't need much, as it usually comes in a mannitol dispersion if memory serves. Also, cyanocobalamin will grant your product a psychedelic yellow color, just so you know. (An aside: a LOT of materials are incompatible with ascorbic acid. That's almost a cliche'.)
  • PerryPerry Administrator, Professional Chemist
    @chemicalmatt - I remember once we were looking for a new vitamin to add to Tresemme conditioner. I added cyanocobalamin at 0.01% as was standard for that line and put the formula in our system before I actually made a prototype. It was fine in the lab but in production it turned a little pink. I had to drop the level to 0.001% to get back to my white color.

  • SibechSibech Member, Professional Chemist
    @chemicalmatt - Valid point - Isn't the psychedelic yellow of the vitamin Bs Riboflavin?

    Regarding the colour you will get from cyanocobalamin, it actually depends on the oxidation state of the cobalt atom. Pink is the natural state Co(III) & Yellow-ish is Co(II). Where Co(III) is the natural state in B12.
    Dabbling Formulator — Qualified Cosmetic Safety Assessor — experienced in claim substantiation & EU regulatory affairs.
  • DoreenDoreen Member
    edited June 8
    @Perry @Pharma @Sibech @chemicalmatt @amitvedakar
    Thank you all so much for your answers!

    You wanted me to clarify the first question ‘1. Does anyone know how stable OH-cobalamine is in an emulsion?’
    What I mean with ‘stable’:  how easily  is the substance decomposed, oxidized.
    I know that OH-cobalamine (also) needs to be protected against light, so that’s one thing.

    I would  expect an emulsion with 0.07% to turn pink as both cyano- & OH-cobalamine are bright red in colour and a red colorant was used in the double blind research to make the placebo look exactly the same.
    There are many incompatabilities known with pharmaceutical substances, like diazepam, fentanyl, lidocaine etc,but  I wondered if there are incompatabilities known with excipients like emulsifiers, preservatives. 

    Both cyano- as OH-cobalamine injections are indeed buffered. Not all manufacturers use the same excipients though.
    Are you sure you aren’t confused with another substance, regarding painful injections? OH-cobalamine is incompatible with lidocaine and (unless used for cyanide intoxication) never administered intravenously, only intramuscular and subcutaneous.
    I have to inject myself i.m. with B12 every three months (I’m a vegetarian + a thyroid disfunction which usually goes together with troubled B12 uptake, enteral pathway of B12 is complicated) and I can’t really say that it’s painful. At least not as notorious as propofol for example, which burns down the veins even with lidocaine (what I remember from being anesthetized decades ago).
    A strange (but explainable) side effect of B12 injections: a lot (1 in 10) of users get acneiform dermatitis (luckily I’m not one of them). Hopefully this won’t happen when used topically to the family member that I will be making it for.
    (@Sibech you're right, I typed this answer + scheme when I only got answers from Perry and Pharma)

    I made a quick scheme.

    Availability and price
    1. Cyanocobalamine :
    - injections only used for Schillingtest i.m.;
    - most (or only) used B12 form for topical application at 0.07%;
    - powder form available on local DIY site, but extremely pricey.
    2. OH-cobalamine:
    - injections only used for B12 deficiency  i.m./s.c. and cyanide/smoke poisoning (i.v.);
    - solution for injection (0.5 mg/ml) available, these are rather cheap.

    Interactions/incompatabilities
    - Incompatibility with several pharmaceutical substances, but no corticosteroids were listed, so I guess there are either no known interactions or it’s unknown (family member uses topical corticosteroids during severe outbreaks);
    - Interaction with vitamin C.

    Side effects
    - Acneiform dermatitis when used parenterally in both lower and higher doses, topically unknown;
    - (FYI for all readers of this forum): When used in large doses (≥ 5 gram parenterally):
    several (serious) side effects mentioned, like raising of blood pressure, ventriculair extrasystoles (‘extra’ heartbeats, paradoxically seems to feel like heart is ‘missing’ a beat), high levels of calcium oxalate in urine (kidney stones), acute kidney failure and necrosis, lowering % of lymphocytes, restlessness, pleural effusion (excessive fluids around the lungs), dyspnoe (shortage of breath), reversible red discoloration of skin and mucous membranes, chromaturia (red discoloration urine), pustular exanthema, peripheral oedema, gastrointestinal symptoms like diarrhea, nausea, effect on laboratory tests: raised glucose, cholesterol, albumin, protein, creatinine and lowered amylase and ALAT (=liver enzyme).
    (The side effects on the kidneys (-failure and -necrosis) were perceived in patients that were treated with high levels of B12 ánd suspected or diagnosed with cyanide poisoning, all the other symptoms (also) perceived in healthy patients.)
    May this be a reminder for everyone not to overdo when using vitamin supplements (especially parenterally).

    Recommended dose
    I will go with the 0.07% topical cyanocobalamine used in the researches.
    I guess I can use 0.07% OH-cobalamine as well. Difference in dose between two forms should be negligible.

    Stability
    Protect against light

    I will be using OH-cobalamine solution for injections 0.5 mg/ml.
    Excipients used in the solution:
    - hydrochloric acid, NaCl, water for injections (Takeda)
    - acetic acid and NaOH, NaCl, water for injections, benzyl alcohol (Centrafarm)

    I’ll use the ampoules from Takeda, as these have less excipients and don’t need to be stored in the fridge.

    I'll first try to make it without a buffer at a pH of about 6.
    (Thanks Sibech and chemicalmatt for your help!!)

    And I’ll weigh the solution first so I can go with % w/w instead of w/v .

    Regarding red colorants: I've tried Gromwell root (CO2) extract a while ago. I needed only the tiniest speck to turn almost half a kilogram of emulsion from white into pink. (It should turn into a blue hue when the product is alkaline instead of neutral or acidic.)

    Edit: adjusted lay-out
  • DoreenDoreen Member
    I misspelled some symptoms (Dutch instead of English).

    I also want to thank Pharma and amitvedekar for info about buffers and pH (I see I only mentioned Sibech and chemicalmatt). I've been too hasty, it's terribly late (or actually very early) here and I'm in dire need of sleep. :flushed: ;)
    And thank ALL of you who have replied, I really value your input very, very much!

    I'll keep you informed about how things went!
  • PharmaPharma Member, Pharmacist
    Good morning @Doreen
    Naw, I'm not mistaken. What I didn't point out explicitly is that lidocaine and B12 come as separate products/vials and are only mixed in the syringe. And you're correct, it an i.m. injection, never i.v. (did I write i.v.?).
  • DoreenDoreen Member
    edited June 8
    @Pharma
    Maybe it's the form that matters (hydroxo or cyano), regarding incompatability with lidocaine? I read the warning not to use hydroxocobalamine together with i.a. lidocaine in the same IV line (and thus couldn't be mixed in the same syringe either) due to 'chemical incompatability' in the Cyanokit booklet (page 23)
    The i.m. injection isn't painful at all though?
  • PharmaPharma Member, Pharmacist
    The cyanokit is something completely different and can not be compared with a standard B12 injection used to treat B12 deficiency ;) .
    Burning during and shortly after a B12 i.m. injection is an often observed adverse effect. It's not always happening, I do know people who don't feel anything at all (except a prick in the beginning) but most do complain to a degree.
  • DoreenDoreen Member
    @Pharma
    The Cyanokit is exactly the same. ;) It's hydoxocobalamine in a higher dose.
  • PharmaPharma Member, Pharmacist
    Higher concentration, more volume, slow injection, i.v. line etc. make it something completely different from mixing two diluted vials for immediate i.m. injection ;) . There's so much more that could go wrong in the former case (including a life).
  • DoreenDoreen Member
    @Pharma
    So? I have never seen two incompatible substances being put together in one syringe, nor for immediate i.m. use or otherwise.
  • DoreenDoreen Member
    @Pharma What I meant in my earlier reply was that maybe one of the forms has the lidocaine incompatibility (OH-), maybe the other, cyano- hasn't? And that the latter form is used in the i.m. injections that you mention? Again, I really can't imagine two incompatible substances that might give precipitation when put together, being mixed in one syringe.

    @Belassi
    You mentioned availability of the B12.
    For me it's the cheapest way to use the solution for injection in hydroxocobalamine form (in the research they used cyanocobalamine, but the powder is quite expensive here). If you can't find the pure powders, maybe you can get hold of the injection solution too? Just a tip.
  • PharmaPharma Member, Pharmacist
    edited June 10
    It's simple: The incompatibility is a pure problem of solubility. The higher the concentration, the more likely it is that something precipitates. The longer such a mixture hangs around, the larger eventual crystals grow. Also, large volumes slowly dripping through valves and a small hollow needle have it clog more easily than manually and quickly forcing 2 ml through just a needle. Also, small crystals in a muscle of an otherwise healthy patient are tolerable whereas many crystals circulating in the blood stream of a patient who's already fighting for his life isn't.
    I've never seen precipitates forming when mixing and injecting B12/lidocaine.
    BTW, if it did, then it's easy and no real loss to just ditch the syringe and start anew whereas a cyanokit infusion isn't that easily re-applied without additional worries arising. The patient groups to which both products are applied have a huge influence on what kind of possible interaction can or can not be tolerated. In this context, it's not just about theoretical chemistry/physics but about people.
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