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  • Discussion - Polarity of emollient and Active ingredients

    Posted by alan123 on April 26, 2020 at 2:07 pm

    I am reading about this and i find it interesting to share. Does it apply in the cosmetic lotion?

    “The optimal polarity of a formulation can now be realized
    by mixing a primary emollient with a low RPI [relative polarity index] (hence a high solubility of the active
    ingredient in that emollient) with a secondary emollient with a high RPI (hence
    a low solubility of the active ingredient in that emollient but therefore with high
    driving force to leave the emollient) in the right proportions to achieve the best of
    both worlds, that is, a high solubility and a high driving force. (…)
    Experimentally, one uses a primary emollient with a small RPI (i.e., with a
    polarity that is very similar to the active ingredient that one wants to formulate) to
    dissolve the desired amount of active ingredient (green arrow in Fig. 4) and then
    adds a secondary emollient with a large RPI (i.e., with a polarity that is very different from the active ingredient that one wants to formulate) to maximize the driving
    force for diffusion (red arrow).  
    (…)

    Pharma replied 2 years, 9 months ago 3 Members · 7 Replies
  • 7 Replies
  • Perry

    Member
    April 26, 2020 at 3:02 pm

    Lab tests are interesting and quite helpful for making claims. But they typically have no real world application because consumers are not good at noticing differences.  What does it mean that there was a 3.2 fold increase in clinical efficacy?  What do they mean by clinical efficacy?

  • alan123

    Member
    April 26, 2020 at 3:46 pm

    “SKIN DELIVERY AND CLINICAL EVIDENCE VALIDATING THE FORMULATING
    FOR EFFICACY CONCEPT

    We have used the formulating for efficacy concept to make skin delivery–optimized
    formulations containing octadecenedioic acid, a novel skin whitener. Formulation
    A was made without using the Formulation for Efficacy concept and contained
    2% active ingredient. Formulation B was made using the formulating for efficacy
    concept and also contained 2% octadecenedioic acid. The exact composition of the
    formulations is provided in Table 1. The only difference between the formulations
    is the choice of the emollients. Propylene glycol isostearate is used as the primary
    emollient in formulation B, whereas triethylhexanoin was used as the secondary
    emollient. Skin delivery experiments using the two formulations on full-thickness
    pig skin were performed and showed a statistically significant, 3.5-fold increase in
    dermal delivery (Fig. 5) (5).
    The delivery result (Fig. 5) illustrates that the formulating for efficacy concept
    delivers significantly more octadecenedioic acid into the skin. The fact that this increase was 3.5-fold is accidental because this depends on the extent of skin delivery
    from the formulation that was not optimized for skin delivery. Therefore, it cannot
    in general be stated by what factor skin delivery will increase using the formulating
    for efficacy concept. But both formulations contained 2% active, yet the delivery was
    much more effective from the second optimized formulation.
    (…)
     In both studies, 20 subjects applied either formulation
    A or B for a period of eight weeks twice a day.
    The chromameter measures the L, a,
    and b values that characterize the color of any object. The L scale is the luminosity scale and its extreme colors are black and white; the ΔL value represents the color
    difference on the L scale relative to the start of the study. The results of these two
    studies are compared in Figure 6.
    The skin delivery–optimized formulation B showed not only an increased skin
    delivery but also an increased skin efficacy. Theoretically, there should be a direct
    correlation between skin delivery and clinical efficacy, and this was confirmed in the
    enhancement factors, 3.5-fold for skin delivery and 3.2-fold for clinical efficacy.
    (…)
    However, there is more that the formulating for efficacy concept can achieve.
    In a delivery-optimized formulation, it is the ratio between the primary emollient,
    the secondary emollient, and the drug, active ingredient, or cosmeceutical that optimizes the flux of the penetrant relative to its concentration. What will happen to
    the skin delivery of the active ingredient if the percentage of the oil phase is reduced
    and in doing so the amount of a lipophilic active in the formulation is also reduced?
    Because the ratio between the three constituents of the oil phase is not changed by
    this reduction, delivery expressed as μg/cm2
    /hr should remain the same, although
    delivery expressed as a percentage would increase.
    To prove this point, a third formulation was prepared, formulation C, in which
    the oil phase was halved relative to formulation B (see Table 1 for composition), and
    this formulation was also clinically tested for its skin whitening efficacy. The clinical
    results of formulations A, B, and C are shown in Figure 7. Relative to formulation
    A (which contained 2% octadecenedioic acid and was not optimized for skin delivery), the clinical effect of formulation C (which contained 1% octadecenedioic acid
    but was optimized for skin delivery) was enhanced by a factor of 3.9. There was no
    statistically significant difference in clinical efficacy between formulations B and C, whereas there was between formulations A and B (P < 0.05) and formulations A and
    C (P < 0.002). This proves that it is the ratio between drug, primary emollient, and
    secondary emollient that is of importance, and not the absolute concentration of the
    drug in a formulation, that determines the clinical efficacy. However, this does not
    mean that one can infinitely reduce the concentration of the cosmeceutical in the
    formulation because there will be point that there is simply not enough drug left in
    the vehicle to obtain the minimum effective concentration at the target site. Studies in which the concentration is continuously reduced, that is, from 1.0% down to
    0.05% octadecenedioic acid, are underway to determine the optimal concentration
    in the formulation. The optimal concentration (or OC100) in the formulation is defined here as the minimum concentration of the active ingredient at which maximal
    efficacy can be obtained and should not be confused with the minimum effective
    concentration (or MEC) at the target site(…)”

  • alan123

    Member
    April 26, 2020 at 3:50 pm

    An idea to have 2+active ingredients matching 2+ main emollients +  and a third emollient with high RPI 

  • Perry

    Member
    April 26, 2020 at 5:42 pm

    I’m not disputing the findings and even with more explanation the strategy sounds interesting.

    However, there are lots of interesting things in a lab that have no real world application. This study is a good example. 

    First, the gold standard for skin lightening is Hydroquinone. Why wouldn’t this study have been done using an ingredient that is actually used in effective products on the market? It would be particularly interesting for that since there are safety concerns with HQ. If it could get the same effects with a lower level, this would be of commercial interest. Optimizing an active that no one uses seems pointless, for product development anyway.

    Also, the Lab measurement is useful for claims but how does it correlate with consumer perception? After 8 weeks of use would a consumer notice any difference?

    These are the types of challenges that researchers have to answer when taking findings from a lab to real world cosmetic formulating. 

  • Pharma

    Member
    April 26, 2020 at 7:55 pm
    First, I didn’t read the whole copy-paste.
    Second, I don’t agree with everything @Perry says. Sure, scientists too often use things which are not directly transferable to an everyday use. But this here is fundamental research, proof of principle. It’s not about developing something for industries or consumers but create basic knowledge and a deeper understanding which, somewhere down the line, helps others to adapt it to more mundane uses.
    Octadecenedioic acid is actually used, just not mainstream. It’s way more interesting than hydroquinone for several reasons: It’s new (= more likelihood for being the first to publish), it’s mechanism of action is new (= more reads), solubility in products contradicts skin penetration (= challenge). A more suitable alternative would be azelaic acid due to comparable difficulties with solubility.
    Anyway, the study is heavily flawed for other reasons. Either they deliberately cheat to boost sales and substantiate marketing (if authors = company selling product = I just changed my mind and am all with @Perry) or they are just researchers who didn’t think fare enough or have not much clue about galenic formulations and skin physiology. I suspect the latter.
    Comparing formulation A with B is not representative because the used emollients are VERY different in how they affect skin barrier, a very poor choice a good scientist wouldn’t do. Since there is neither a link nor a full title to the study, I don’t know whether they specify what the SE in glyceryl stearate SE is (something a smart person would do, a smarter one wouldn’t use an emulsifier in one formulation and omit it in the other). Besides, studies on the influence of solubility of pharmaceutical drugs for dermal delivery are anything but new or innovative. That factor of about 3-4 may be statistically significant but it’s just okayish. A factor of 10 (on penetration, not bleaching) would be the least I’d judge worthy of publishing even as proof of concept. Besides, their concept is somewhat against the current dogma without proving it wrong. It’s more of a misinterpretation which shows that different solvents may have different effects… but that finding is an old hat.
    Again, I can’t read the original paper and hence, it’s difficult to really judge. Ranting is easy ;) .
  • alan123

    Member
    April 26, 2020 at 8:37 pm

    Source - Dermatologic,
    Cosmeceutic, and
    Cosmetic Development
    Therapeutic and Novel Approaches - Edited by
    Kenneth A. Walters
    An-eX Analytical Services Ltd.
    Cardiff, United Kingdom
    Michael S. Roberts
    School of Medicine, University of Queensland
    Princess Alexandra Hospital
    Buranda, Australia 

    https://www.amazon.com/Dermatologic-Cosmeceutic-Cosmetic-Development-Therapeutic/dp/0849375894

  • Perry

    Member
    April 27, 2020 at 1:21 pm

    @Pharma - Nice analysis. I do think you’ve misunderstood my objections so perhaps what I wrote didn’t convey it properly. 

    I’m all for basic research. I think it is great to discover fundamental truths and they certainly can eventually have an impact on formulating. I just think too often researchers (or perhaps marketers) jump from an interesting discovery in a lab to claims of producing radically improved cosmetic formulas without doing the necessary application/development work in between. 

  • Pharma

    Member
    April 27, 2020 at 7:02 pm
    Now, I’ve found the original publication referenced in that book.
    Managed to get a copy of it and read a bit. Turns out that the book may be misleading or give a wrong idea (although that book is intended as scientific inspiration, not a formulation guide). It’s also easy to read and meant as a proof of concept using arbutin and octadecenedioic acid as theoretical examples. The latter was then used for a trial formulation with the intention to show that they could really predict the outcome from theoretical considerations regarding driving forces for skin penetration of active ingredients. Apart from me still being not happy with their choice of ingredients and lack of appropriate controls (which would have been overkill for their aim), the publication is good for what it is intended to be and does not claim more than there is.
    Notably, the proposed formulations can not be copied/used for anything other than octadecenedioic acid but their calculations (with emphasis on polarity) can be used as starting point for more efficient formulations. And that’s exactly what basic research is all about.
    BTW I don’t know how new their insights are. The single theories are fairly old but, as they mentioned too, are often not put together and neglected in cosmetics development. They are however considered by pharmaceutical companies, if I’m not mistaken.