Collagen supplement

Abstract

A collagen-boosting supplement that contains at least 4, optionally at least 10, collagen building block amino acids and is substantially free of histidine. The building block amino acids may be selected from: Glycine, L-Proline, L-Hydroxyproline, L-Glutamic Acid, L-Alanine, L-Arginine, L-Aspartic Acid, L-Serine, L-Leucine, L-Lysine, L-Hydroxylysine, L-Valine, L-Phenylalanine, L-Threonine, L-Isoleucine, L-Methionine, and L-Tyrosine. The supplement may further comprise: vitamin C; one or more mast cell stabilisers which may be selected from: quercetin, molybdenum, bromelain, DAO (diamine oxidase), Urtica Dioica (stinging nettle), Nigella Sativa (black cumin), Zingiber (ginger), Scutellaria baicalensis (Chinese skullcap), Sambucus (Elderberry), Aloe Vera, Syzygium aromaticum (clove), and matcha; one or more collagen-strengthening herbs which may be selected from: Bilberry, Centella, and Astragulus; one or more Glucosaminoglycans (GAGs) which may be selected from: Hyaluronic acid, glucosamine, and chondroitin; one or more antioxidants which may be selected from: astaxanthin and resveratrol; and / or one or more cofactors which may be selected from: zinc, biotin, silicon, manganese, magnesium, Vitamin D, Vitamin A, Vitamin E, and iron. The supplement may be a foodstuff, medicament, nutraceutical, or cosmetic. The supplement may be used to treat hypermobile Ehlers-Danlos syndrome (hEDS) while reducing the likelihood of mast cell degranulation through histamine activation.

Description

Field of the Invention The present invention relates to a formulation for a collagen supplement that offers collagen support, while also, in this specific case, eliminating the potential for an adverse histamine response. Background section (i) Background on the disease Hypermobile Ehlers-Danlos syndrome (hEDS) is a condition affecting approximately 1 out of every 5,000 people (MedlinePlus: Ehlers-Danlos syndrome 2022). A collagen defect, hEDS can affect all collagenous tissue and therefore joint, bone, skin, nerve, digestive and vascular health. While hEDS is regarded as a genetic condition, the genetic cause is unknown, and the implicated gene(s) have not been identified to date. Collagen is an important structural protein found in the extracellular matrix, composed of sequences of amino-acids giving rise to 16 different types of collagen (6ofthem (I, II, III, IV, V and X) comprising 99% of all collagen in the human body, with type I alone comprising 90%). Damage to the collagen leads to arthritis and joint pain, brittle hair, decrease in bone density, gastrointestinal issues, weaker muscles, and many other degenerative conditions, so collagen support can be extremely beneficial. The amino-acid building blocks are assembled by fibroblasts into the different types of collagen. Patients with hEDS suffer from joint hypermobility, joint instability, chronic pain, osteoporosis, mild skin hyperextensibility, abnormal scarring, chronic fatigue, gastrointestinal issues, headaches, blood pressure disorders, nervous system disturbances and nerve pain. A fundamental issue for this patient population is that hEDS is one of a triad of comorbid conditions: hEDS, MCAS (mast cell activation syndrome), and dysautonomia (sometimes referred to as postural orthostatic tachycardia syndrome or POTS). MCAS is a chronic, ongoing degranulation of mast cells, leading to excessive release of histamine, tryptase, heparin and a mix of other leukotrienes, eicosanoids and cytokines. Dysautonomia is a disorder of the autonomic nervous system that can cause disturbances in heart rate, blood pressure, respiration, digestion, and sexual arousal. While practitioners wait for research to describe the exact mechanisms that link hEDS, MCAS, and dysautonomia, current science points to the interconnectedness of collagen, mast cells and nerves cells. As shown in Figure 1, Mast cells (3), which release histamine, reside in the collagen (1). As -2- shown in Figure 2, mast cells degranulate more easily when irritated by the daily microtears (2) characteristic of unstable collagen, and result in: an increase in circulating histamine (4), damaged local tissue from chronic inflammation, and overburdened histamine detox pathways. Further, a defect in the collagenous tissue impacts the nerves’ ability to signal one another, and mast cells’ chronic histamine release inflames and damages fragile nervous system tissue (5). (ii) How people have previously treated that disease Doctors who support patients with hEDS treat the disease through a combination of additional screenings and scans, pharmaceuticals, physical therapy, surgeries, and cognitive behavioral therapy (CBT). As a relatively rare disease, research on the treatment of hEDS is limited. There is no cure for hEDS, and treatment is focused on support. One of the root causes of the irritated mast cells is collagen instability, so a common sense approach is to support patient collagen production by, for example, making sure that the amino acid building blocks of collagen are readily available in the diet or with supplementation. However, there is a gap in the research, as there are no studies focused on the results of treating hEDS patients with dietary supplementation of collagen. Furthermore, clinically and anecdotally, hEDS patients who aim to support their own collagen production by ingesting collagen report that they cannot tolerate it. This is to be expected as most collagen products on the market, and collagen-rich foods, are high in histidine, which readily converts to histamine and exacerbates the existing histamine burden in the body (which is already elevated in hEDS patients because, as discussed above, mast cells reside in collagen and release histamine in response to the daily microtears that hEDS patients experience). Notably, mast cells also have receptors for histamine, so excess dietary intake of histamine, or its precursor histidine, can trigger mast cells to degranulate. Given the importance of both collagen instability and damage done by chronically degranulating mast cells by the histamine released in Ehlers-Danlos syndrome, what is needed is a product that provides collagen support without exacerbating the histamine burden on the system. Summary of the Invention (iii) Introduction to the invention Hypermobile Ehlers-Danlos syndrome (hEDS) patients should benefit from collagen support, but they are particularly sensitive to increased histamine, which is produced by the amino acid histidine in existing collagen support products. The production of histamine offsets the benefits of the collagen support, because it causes inflammation that damages the vulnerable collagen. The invention is an amino acid formulation that mimics human collagen, but intentionally excludes the use of the amino acid histidine. (iv) Main statement of invention All commercial collagens currently on the market (bovine, marine, chicken, eggshell membrane, and vegan amino acid formulas) have histidine in them (as it is one of the amino acids in collagen), so it makes them potentially irritating to those with the clinical triad of hEDS, MCAS and dysautonomia. Many patients cannot tolerate any of the existing collagens available. So, for the people who need collagen support the most, there are currently no safe options on the market. The applicant thus devised a plant-based collagen alternative which mimics the amino acid profile of human collagen (based on the work of e.g. Eastoe, J. E. 1955) minus the histidine. In the main embodiment, the invention provides a collagen product with a composition comprising of amino acids including several from the list: Glycine, L-Proline, L-Hydroxyproline, L-Glutamic Acid, L-Alanine, L-Arginine, L-Aspartic Acid, L-Serine, L-Leucine, L-Lysine, L-Hydroxylysine, L-Valine, L-Phenylalanine, L-Threonine, L-lsoleucine, L-Methionine, L-Tyrosine wherein the composition is substantially free from histidine (i.e. contains less than 1%, or less than 0.5%, or less than 0.2%, or ideally less than 0.1% histidine). In a further embodiment, the invention provides a collagen product that contains more than 10 amino acids (with low histamine response) to provide effective collagen support for hEDS patients. The higher number of amino acids allows for the uncertainty over the exact mech anism behind the syndrome. The increased number of amino acids will also provide support for other users who do not have hEDS but are seeking collagen support without increasing their histamine burden. (v) Discussion of the subfeatures of the invention The benefits of the low-histamine-response collagen supplement can be improved in a number of ways. The following cofactors, herbs, antioxidants, glycosaminoglycans and mast cell stabilizers have a myriad of beneficial effects on collagen from stabilizing collagen fibers, to promoting collagen biosynthesis, to protecting collagen from degradation during inflammatory processes, to stimulating growth-promoting activity of fibroblasts, to increasing cross-linking of collagen fibers, to preventing enzymatic cleavage of collagen during inflammation and decreasing release of inflammatory mediators (histamine, prostaglandins and leukotrienes) which lead to said cleavage. The addition of Vitamin C (for example L-Ascorbic Acid or Magnesium Ascorbate) helps not only in that Vitamin C is a necessary cofactor required for the formation of collagen (a deficiency leads to scurvy, a disease of collagen production), but also increases rates ofcoilagenesis and is considered a mast cell stabilizer, which means less mast cell degranulation, leading to less histamine, and thus less local inflammation and deterioration of collagen. Vitamin C thus helps both to produce collagen and to protect it (Boyera, N. et al. 1998). The addition of other cofactors such as zinc, biotin, silicon, manganese, magnesium, Vitamin D, Vitamin A, Vitamin E, and iron help with production, crosslinking and mitigation of the effects of inflammation. The addition of GAGs (Glucosaminoglycans) such as hyaluronic acid and Chondroitin) help to create structural support for collagen by providing scaffolding, protection, and cushioning. (Frevert, C., &Wight, T.N. 2006) Chondroitin, notably, also acts as a mast cell stabilizer, which cuts down local inflammation. The addition of anti-oxidants such as astaxanthin, resveratrol, and other anthocyanins and / or flavinoids, helps by scavenging free-radicals which can damage collagen. The addition of mast cell stabilizers and other histamine reducing support such as quercetin (Penissi, A.B., et al. 2003), molybdenum, bromelain, DAO (diamine oxidase), Urtica Dioica (stinging nettle), Nigella Sativa (black cumin), Zingiber (ginger), Scutellaria baicalensis (Chinese skullcap), Sambucus (Elderberry), Aloe Vera, Syzygium aromaticum (clove), and matcha, are beneficial because, as discussed, an important step in breaking the vicious cycle of histamine damaging collagen, which leads to more histamine being released, is to stabilize the cells (mast cells), which release histamine, making them more robust and thus less likely to degranulate. The addition of coIlagen-strengthening and collagenesis-promoting herbs such as Bilberry, Centella, Sambucus, and Crataegus (Hawthorne) helps by stabilizing collagen fibers, strengthening collagen cross-linking, and promoting collagen biosynthesis. As each of these herbs is also high in flavonoids, which impart anti-inflammatory and antioxidant activity, which in turn aid in stabilizing collagen fibers, stabilizing mast cells, and reducing local inflammation. They are widely known to increase the tensile binding strength of connective tissue in general and protect connective tissue against oxidative damage. Arribas-Lopez, et al., expand on these effects in “A Systematic Review of the Effect of Centella asiatica on Wound Healing”, in which they state that “Centella Asiatica has a stimulating effect on collagen I, Fibroblast Growth Factor (FGF) and Vascular Endothelial Growth Factor (VEGF) production. Besides, Centella asiatica has shown an anti-inflammatory effect observed by the reduction in lnterleukin-1 p (IL-1 p), lnterleukin-6 (IL-6) and Tumour Necrosis Factora (TNFa), prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), and lipoxygenase (LOX) activity” (Arribas-Lopez, E. et al. 2022). The supplement could be in the form of a foodstuff, a medicament, a nutraceutical or a cosmetic. Examples (vi) Example 1 The invention is an amino acid formulation that mimics human collagen, with the critical omission of the amino acid histidine. The aim is to provide hEDS patients with a formulation that increases collagen production, without increasing histamine levels. The hypothesis is that by excluding histidine (which turns to histamine in the body) from the formula, the invention provides hEDS patients and anyone else suffering with unstable collagen or a reduction in collagen production with support for collagen production without histamine, a key actor in the cycle of damaged collagenous tissue, degranulating mast ceils, histamine release, inflammation (leading to further damage to the collagenous tissue) and compromised fragile nerve tissue. The aim is to disrupt this cycle by supporting more robust collagenous tissue, stabilizing mast cells, towering histamine levels, decreasing inflammation, and allowing for the repair of nerve and coilagenous tissue. While studies show that supplementation of just one to three of the 18 amino acids of which collagen is composed (at the right dosage and frequency) increases collagen production, the invention incorporates upto 16 of the amino acids in collagen, to ensure that it is providing the best support. As the gene or genes responsible for hEDS are not yet known, the aim is to create a dietary supplement that provides as many of the amino acids in collagen as possible. For example, a collagen supplement that contains any of the following amino acids: Glycine, L-Proline, L-Hydroxyproline, L-Glutamic Acid, L-Alanine, L-Arginine, L-Aspartic Acid, L-Serine, L-Leucine, L-Lysine, L-Hydroxylysine, L-Valine, L-Phenylalanine, L-Threonine, L-lsoleucine, L-Methionine, and L-Tyrosine will support the collagen, without producing the histamine response, that would be harmful to those with MCAS, as long as it does not also contain histidine. It is not possible to extract the histamine from the animal sources of collagen supplement usually used, so the compositions would be made of amino acids derived from corn, and, as such, are inherently vegan, and thus will be of benefit to the vegan population, particularly those suffering from collagen and / or histamine problems. The capsule delivery method has been chosen to avoid the need for the additional sweeteners and flavors that make amino acids palatable in powder form, but that are potentially irritating, especially to those with hEDS and MCAS. Currently, all collagen formulations from animal sources, as well as all vegan collagen formulations that mimic the amino acid profile of human collagen, include histidine. As histidine readily converts to histamine, which is then known to activate mast cells to release more histamine, these formulations do not achieve the goal of the current invention: to increase collagen production in the body whilst decreasing mast cell activation and histamine levels. White there is no known cure for patients with hEDS, research on healthy cohorts indicates that nutritional and dietary support that increases collagen levels without simultaneously increasing histamine levels should improve collagen biosynthesis and functionality, thus alleviating symptoms and improving quality of life. 5 (vii) Examples of specific formulations An example formulation is shown in Table 1 below. Table 1 Ingredient Recommended daily intake (milligrams) Glycine 960 L-proline 576 L-Hydroxyproline 474 L-Glutamic acid 420 L-Alanine 390 L-Arganine 336 L-Aspartic acid 258 L-Ascorbic acid (Vitamin C) 150 L-Serine 150 L-Leucine 132 L-Lysine 120 L-Valine 114 L-Phenylalanine 90 L-Threonine 84 L-lsoleucine 72 Magnesium Ascorbate (Vitamin C) 60 L-Methionine 36 L-Tyrosine 24 -7- Typically these would be derived from com and turned into free-form amino acids to make them readily digestible. References Afrin, L. B., Ackerley, M. B., Bluestein, L. S., Brewer, J. H., Brook, J. B., Buchanan, A. D., Cuni, J. R., Davey, W. P., Dempsey, T. T., Dorff, S. R., Dubravec, M. S., Guggenheim, A. G., Hindman, K. J., Hoffman, B., Kaufman, D. L., Kratzer, S. J., Lee, T. M., Marantz, M. S., Maxwell, A. J., McCann, K. K., ... Molderings, G. J. (2020). Diagnosis of mast cell activation syndrome: a global "consensus-2". Diagnosis (Berlin, Germany), 8(2), 137-152. Available from: https: / / doi.org / 10.1515 / dx-2020-0005 Arribas-Lopez, E., Z and, N., Ojo, O., Snowden, M. J., &Kochhar, T. (2022). A Systematic Review of the Effect of Centella asiatica on Wound Healing, International journal of environmental research and public health, 19(6), 3266. Available from: https: / / doi.org / 10.3390 / ijerph19063266 Boyera, N., Galey, I., &Bernard, B. A. (1998). Effect of vitamin C and its derivatives on collagen synthesis and cross-linking by normal human fibroblasts. International journal of cosmetic science, 20(3), 151-158. Available from: https: / / doi.Org / 10.1046 / j.1467-2494.1998.171747.x) Eastoe, J. E. (1955). The amino acid composition of mammalian collagen and gelatin. The Biochemical journal, 61 4, 589-600 Frevert, C., &Wight, T. N. (2006). Extracellular Matrix: Matrix Proteoglycans. Encyclopedia of Respiratory Medicine. MedlinePlus [Internet], Bethesda (MD): National Library of Medicine (US); [updated 2022 July 29], Ehlers-Danlos syndrome. Available from: https: / / medHnep|gs.g.9.^^ Penissi, A. B.. Rudolph, M. I,, &Piezzi, R. S (2003). Rote of mast cells in gastrointestinal mucosal defense. Biocell: official journal of the Sociedades Latinoamerteanas de Microscopia Electronica ... et. al, 27(2), 163-172.

Claims

1. A collagen boosting supplement that contains at least 4 collagen building block amino acids and is substantially free of histidine.

2. A collagen boosting supplement according to claim 1 wherein the histidine content is less than 1%, more preferably less than 0.5%, more preferably less than 0.2%, or more preferably less than 0.1 %.

3. A collagen boosting supplement according to claim 1 or claim 2 wherein the collagen building block amino acids are selected from: Glycine, L-Proline, L-Hydroxyproline, L-Glutamic Acid, L-Alanine, L-Arginine, L-Aspartic Acid, L-Serine, L-Leucine, L-Lysine, L-Hydroxylysine, L-Valine, L-Phenylalanine, L-Threonine, L-lsoleucine, L-Methionine, and L-Tyrosine.

4. A collagen boosting supplement according to any preceding claim and further containing vitamin C.

5. A collagen boosting supplement according to claim 4 wherein the vitamin C content is greater than 0.1%, more preferably greater than 0.5%, more preferably greater than 1%, or more preferably greater than 4%.

6. A collagen boosting supplement according to any preceding claim that contains at least 5 collagen building block amino acids.

7. A collagen boosting supplement according to any preceding claim that contains at least 10 collagen building block amino acids.

8. A collagen boosting supplement according to any preceding claims wherein the collagen building block amino acids include glycine and L-proline.

9. A collagen boosting supplement according to claim 8 wherein the collagen building block amino acids include L-hydroxyproline.

10. A collagen boosting supplement according to any preceding claim wherein the collagen building block amino acids include L-Hydroxylysine.

11. A collagen boosting supplement as claimed in any of the preceding claims, further comprising one or more mast cell stabilisers.

12. A collagen boosting supplement according to claim 11 wherein the one or more mast cell stabilisers are selected from the list comprising: quercetin, molybdenum, bromelain, DAO (diamine oxidase), Urtica Dioica (stinging nettle), Nigella Sativa (black cumin), Zingiber (ginger), Scutellaria baicalensis (Chinese skullcap), Sambucus (Elderberry), Aloe Vera, Syzygium aromaticum (clove), and matcha.

13. A collagen boosting supplement as claimed in any of the preceding claims further comprising one or more collagen-strengthening herbs.

14. A collage boosting supplement according to claim 13 wherein the one or more collagen-strengthening herbs are selected from the list comprising: Bilberry, Centella, and Astragulus.5 15. A collagen boosting supplement as claimed in any of the preceding claims, further comprising one or more Glucosaminoglycans (GAGs).

16. A collage boosting supplement according to claim 15 wherein the one or more GAGs is selected from the list comprising: Hyaluronic acid, glucosamine, and chondroitin.

17. A collagen boosting supplement as claimed in any of the preceding claims, further comprising one 10 or more antioxidants.

18. A collage boosting supplement according to claim 17 wherein the one or more antioxidants is selected from the list comprising: astaxanthin and resveratrol.

19. A collagen boosting supplement as claimed in any of the preceding claims, further comprising one or more cofactors:15 20. A collagen boosting supplement according to claim 19 wherein the one or more cofactors is selected from the list comprising: zinc, biotin, silicon, manganese, magnesium, Vitamin D, Vitamin A, Vitamin E, and iron.

21. A collagen boosting supplement as claimed in any of the preceding claims, wherein the composition is a foodstuff, medicament, nutraceutical or cosmetic.

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