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Preservative for Oral Mucosa Use
Hello All. Can you recommend to me a food-grade preservative that even when used with a permeation enhancer is non-toxic to humans? I have investigated several preservatives that are allowed for oral use (according to the manufacturer) and is food-grade to have some degree of confidence that the formula will not have toxic effects when the presence of permeation enhancer in the formula can increase its bioavailability, but I am still not sure which one is the best. I am working with a final pH of 3.5-5.5
Summary of Requirements:
1. Efficacy around a pH of 3.5-5.5
2. Non-toxic to humans even when its bioavailability is increased by the presence of permeation enhancers in the formula. As you know, permeation enhancers will not only increase the bioavailability of active ingredients, it will also increase the bioavailability of all components in the formula. Size and structure can be a limiting factor as well. But, a lot of preservatives have a molecular size of less than 500 daltons. So, searching for a non-toxic one is a must.
3. Broad Spectrum Preservative - can handle gram + and - bacteria, yeast, mold, and other infectious species like B. Cepacia, etc.
1st Option - Euxyl K712, MicroCare SB, Saliguard SP > Main Component: Sodium Benzoate and Potassium Sorbate. > Comment: According to a data sheet I read, Benzoic Acid and Benzoates, Sorbic Acid and Sorbates, Organic Alcohols, have limited efficacy in bacteria and is more efficacious in controlling yeast and moulds.
2nd Option: Sepicide G > Main Component: Glycerine and Ethyl Lauroyl Arginate HCL >> Comment: This one has a good performance according to its datasheet and safety is not an issue but the performance is reduced by the presence of anionic ingredients - which I do have in the formula.
Other Options:
Geogard 221 - Dehydroacetic Acid, Benzyl Alcohol, Aqua
Geogard Ultra - Gluconolactone, Sodium Benzoate
Cosmocil CQ - Polyaminopropyl Biguanide
Geogard LSB - Levilinic Acid, Sorbic Acid, Benzoic Acid
TroyCare RPP37 - Ethylhexylglycerin, Phenylpropanol
@Philip Geis: You’re one of the people I look up to. I am really amazed by your expertise in microbiological control. If you can read this post, it would mean a lot to me if you will comment on this and give me some guidance.
Others: Please feel free to comment. I will take into consideration all comments.
I am also accepting reading assignments if you have books that can answer my questions.
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7 Replies
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consider benzoate, parabens.
can you describe product and formula?
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😮 Wow, thank you so much, Dr. Geis. It’s a pleasure to be able to talk to you in this forum.
Let me tell you more about my formula and the help I need. Also, please feel free to correct me if any part of my understanding is off.
I’m working with chemical actives that need to bypass the stratum corneum to be effective. To do this, I use a permeation enhancer like bis-ethoxydiglycol-cyclohexane 1,4 dicarboxylate combined with osmolytes to help these actives penetrate the skin. However, the challenge is that permeation enhancers don’t just selectively increase the bioavailability of the active ingredients—they also enhance the absorption of all the ingredients in the formula.
In general, chemicals with a molecular weight under 500 daltons can permeate the skin more easily when permeation enhancers are used - assuming there aren’t any structural issues with the molecules. So, by increasing the bioavailability of the active ingredients, I’m also increasing the bioavailability of preservatives, which are typically under 500 daltons in size. If I increase the bioavailability of preservatives, I could face potential safety concerns related to toxicity.
I’m currently looking for a broad-spectrum preservative that would be biocompatible with humans, even if absorbed systemically, or at least non-toxic. My formulation is a cream/lotion with a final pH range of 3.8–5.5 (including any pH drift), with the final pH around 4.5–4.7.
I’ve read various brochures from different manufacturers, information sheets, and modules from the cosmetic formulation course I’ve taken at the Institute where I study cosmetic chemistry. I’ve also reviewed the book you are the chief editor of, Cosmetic Microbiology: A Practical Approach (third edition), though I haven’t finished it yet. In my search for an effective preservative system with minimal toxicity, I’ve come across the following information:
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Sorbates, Benzoates, and derivatives are used in food preservation, often alongside other preservation methods like QACs, refrigeration, and water availability manipulation. From this, I concluded that since these are food-grade ingredients, systemic absorption is unlikely to cause toxicity in humans. Of course, I’ll still follow regulatory limits for all cosmetic ingredients.
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Dehydroacetic Acid is allowed in oral care products, according to the Geogard 111A brochure [INCI Name: Dehydroacetic Acid], with a recommended use level of 0.1–0.6% w/w.
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Organic Acids are effective against Gram-positive bacteria, yeast, and molds but have limited efficacy against Gram-negative bacteria (which are more common in water-based systems). To address Gram-negative bacteria, organic acids are often paired with other preservatives like phenoxyethanol, MCIT, or formaldehyde releasers.
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Chelators can improve the efficacy of preservatives.
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Ethylhexylglycerin enhances the effectiveness of phenoxyethanol.
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It’s ideal to have a pKa value that is less than or equal the pKa value of organic acids in order for it to perform at its best:
- Benzoic acid: pKa 4.2
- Dehydroacetic acid: pKa 5.26
- Sorbic acid: pKa 4.76
- Sodium dehydroacetate: pKa 5.36
- Potassium sorbate: pKa 4.69
- Sodium benzoate: pKa 4.08
Hurdles:<div>
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Euxyl K712 contains potassium sorbate, sodium benzoate, and water.
I’d prefer to use it as an antifungal and antibacterial agent against Gram-positive bacteria. According to your book, it works best when paired with phenoxyethanol, methylchloroisothiazolinone (MIT), or formaldehyde releasers. However, I can’t use MIT because of its sensitization issues in leave-on products, and I can’t use formaldehyde releasers due to the potential risk of increasing formaldehyde bioavailability, which could raise concerns about carcinogen exposure. As far as I know, as long as it’s used within regulatory limits, formaldehyde releasers are considered safe, but because permeation enhancers increase bioavailability, I don’t want to take the risk.
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Sorbic acid is also food-grade but can degrade in the presence of glycerol and some salts, which are in my formula. So, I can’t use sorbic acid either.
Other preservatives that can be used around the mouth:
Sepicide G - made up of Glycerin and Ethyl Laurol Arginate > the problem with this is that efficacy is reduced by the presence of anionic ingredients.
TroyCare EPP37 - made up of ethylhexylglycerin + phenylpropanol > I don’t know much about the bactiricidal/bacteristatic or fungicidal/static efficacy of phenylpropanol. I also don’t know if it is effective against gram + and/or - bacteria?
Geogard Ultra - made of gluconolactone, sodium benzoate > not sure if this is still safe when the bioavailability is increased by permeation enhancers. Not also sure if it is effective against gram + and/or - bacteria?
Final Verdict:</div><div>
For a robust preservative system in my case, I’m considering:
Euxyl K712 + phenoxyethanol + ethylhexylglycerin + chelator. This combination should effectively target Gram-positive and Gram-negative bacteria, yeast, and mold. But I want to confirm whether this system would still be non-toxic when bioavailability is increased? Is my understanding of this combination correct?My logic is that if these ingredients can be safely used in oral care products, they should have a low toxicity profile for humans, especially when used within regulatory limits. But I’m not entirely sure if my logic is correct, so I’d appreciate your thoughts on this.
Dr. Geis, I’d love to hear your comments on my situation. With your bachelor and doctoral degree in microbiology, expertise, and your previous experiences in the US Army and P&G, I am more than confident that I will learn so much from you. Thank you in advance for taking the time to read and respond to my message in this forum.
Please feel free to ask me more questions if you need more information. Additionally, please feel free to correct me if my logic is flawed.
I look forward to your response.
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Good point with the permeation enhancement. Whatever preservative goes on skin will go into tissue. To that, there are very little data for any preservative with the exception of paraben. Parabens do permeate and are impacted by esterases in skin and tissue. A CDC study - a good one as in not Darbre quality - found parabens at exceedingly low levels in urine of typical men. Cosmetic industry generated a lot of sound data that was not published for parabens uptake and excretion that defended typical use. I’m not toxicologist enough to address the concern with assurance but gut feel would look to preservatives used for injectables. I could hook you up with someone if you want.
I’d stay away from the marketed combinations. They’re organized for unique marketing positioning if not patent protection, claim unjustified broad spectrum and wide pH coverage and presume safety of the combination rather than confirm. In context of greatly enhanced permeation, I’d trust none.
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Thank you so much, Dr. Geis, for your input. I totally agree with you. Even after reading a lot of resources and digging into published studies in Google Scholar and other resources, I still couldn’t find much information that can give me a high degree of confidence that what I am formulating has low levels of toxicity while maintaining the highest quality of microbiological control. I also had this gut feeling that something doesn’t add up right, especially that everybody is claiming to be effective even if I have heard that some of my coformulators had seen failed PET with those marketed materials that claim to be broad spectrum.
Yes! I would love to work with that someone that you are referring to as well, just the same way I’d love to collaborate with you. Can you please hook me with that person?
Thank you again, Dr. Geis. I couldn’t thank you enough for your guidance.
I will remain attentive to your response.
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Additionally, I hadn’t really thought of exploring injectables in depth. However, after you mentioned it, I realized they also utilize preservatives to maintain their stability. This strongly suggests that their preservative systems are highly likely robust enough to control microbiological contamination while also being biocompatible with the human body.
This is another scope of preservation that is quite interesting for me as well. I will await further communication from you regarding that another person you have in mind.
Also, if you have more tips for me about things that you have learned from your experiences in the field, I would love to know more about it.
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I’ll make some calls.
btw - it’s :”Phil”.
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Got it. Phil. Thank you.
I will wait for your updates.
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