AU2021221835A1

AU2021221835A1 - Cosmetic base solutions as cosmetic delivery systems, associated cosmetic formulations, and uses thereof

Info

Publication number: AU2021221835A1
Application number: AU2021221835A
Authority: AU
Inventors: Farid Wakim
Original assignee: Phoxmetics Ltd
Current assignee: Phoxmetics Ltd
Priority date: 2021-08-25
Filing date: 2021-08-25
Publication date: 2023-03-16

Abstract

The invention relates generally to reconstitutable cosmetic base composition comprising calcium, magnesium, potassium, sodium and chloride ions, a selection of cosmetically active ingredients, and a buffer such as azelaic acid, wherein once reconstituted the composition is characterised as having a pH of from about 3.5 to about 6. Upon reconstitution, the compositions are used to address cosmetic skin concerns such as dry skin, inflammation, hyperpigmentation, acneic production, ageing and other aesthetic features such as radiance.

Description

COSMETIC BASE COMPOSITIONS AS COSMETIC DELIVERY SYSTEMS, ASSOCIATED COSMETIC FORMULATIONS, AND USES THEREOF FIELD

The invention relates generally to reconstituable cosmetic base composition as a novel cosmetics delivery system and topically applied cosmetic formulations based on said compositions. In particular, the invention relates to cosmetic compositions and formulations, and more particularly, "dermocosmetics", for example, in highly functioning or science-based topical applications to address cosmetic skin concerns such as dry skin, inflammation, hyperpigmentation, acneic production, ageing and other aesthetic features such as radiance.

BACKGROUND

The skin is the largest organ of our body and acts as our physical shield against the external environment, retaining complex structure, function, metabolic action and regulatory processes. There are four predominant layers of dermal tissue including the stratum corneum, epidermis, dermis and adipose tissue. There is a basal layer between the epidermis and dermis which gives rise to cellular communication, signalling and maintains a repository of extracellular proteins.

The pH of healthy skin ranges from 4.8-5.5, and this is maintained precisely. This is due to an acid mantle which is present over the skin's barrier. Pollution, temperature, dermal pathogens and UV exposure disrupts skin function, barrier function, pH value and a subsequent cascade of events may ensue. Dermal protein signalling and the production of growth factors cannot occur optimally in alkaline skin states. Patients with dermatological skin disorders such as eczema or dermatitis have higher pH values which are closer to neutral or slightly alkaline. As a consequence, these patients and their skin are unable to form lipids, ceramides or other integral structural features of the dermal tissue. Moreover, acidity is required for appropriate function and regulation of the skin's microbiome.

The stratum corneum is the uppermost layer, commonly referred to as the barrier, where the skin's microbiomic community reside in unison with corneocytes. Generally, keratinocytes are structured in a manner which prevents external aggressors from entering the skin and again, which is why the term 'barrier' is often used. This is a matrix of intercrossed involucrin and keratohyalin which form the basis of a codified involucre.

Intercellular spaces exist within these matrices or crossed structure where lipids accumulate; simply put, these lamellar lipids 'fill in the gaps'. However, this lipid bi layer contains polar heads and intracellular channels which allow the passing and binding of hydrophilic substances. However, this layer usually presents problems for modern skincare formulations due to this structure and tortuous pathway as described by dermatologists for substances to pass through.

Creams generally possess lipophilic properties and thus, is generally received well by the skin regardless of substance; niacinamide in an aqueous serum will not diffuse as easily, acknowledging evaporation, as niacinamide in an emulsified solution for example.

The epidermis is responsible for pigment creation, holding melanocytes, as well as generalised presence of keratinocytes and other antigen-presenting cells. The dermis is a reservoir of vasculature which innervates the epidermis and is responsible for the production of growth factors and other messenger proteins or enzymes as fibroblasts are abundant within this layer. The adipose tissue resides in the 'bottom' layer which lines the connective tissue network between the dermis and the subcutaneous layer beneath the skin. Most peptides or proteins are housed and transported throughout this connective network including several types of collagen, elastin, fibrin and other glycosaminoglycans. Such peptides are released and processed in the extracellular space in pro-forms; pro collagen 1 is modified via enzymatic processing before complete formation of collagen type 1.

The skin is a complex organ and is affected materially by extrinsic and intrinsic factors which lead to depletion, inflammation, irradiation, degradation or reconstruction, regeneration, rejuvenation and endogenous healing processes. Extrinsic factors are the major cause of ageing within skin, most notably from UVA induced irradiation and further lipid peroxidation. The generation of reactive oxygen species and free radicals pose various issues including induction of matrix metalloproteinase activity, activation of inflammatory pathways such as the NF-kB or TNF-alpha sequences, tyrosinase based action or induction of disordered melanosome function.

The aforementioned effects gives rise to issues including barrier dysfunction, pathogenic material generation via a disordered microbiome which may cause acne, alongside inflammatory pathways which cause acneic production, disordered sebum regulation, degradation of proteins such as collagen and elastin and suppress fibroblast proliferation. Moreover, intrinsic factors such as DNA and telomerase dysfunction shorten these caps or telomeres and remains the biological nature of ageing with loosened DNA coiling and structure.

However, most of these features are gradual, despite their nefarious nature. Dysregulated pH of the skin will result in disorders and dermal complications from very early ages. Modem skincare and evolving advancements have revealed high functioning, scientific and dermatologically based dermocosmetics to address these factors. Genetics play a part in how skin is expressed within an individual, however at least 80% of all skin damage and deterioration is a result of UVA exposure.

Dermocosmetics aim to address these intrinsic and predominantly extrinsic factors which cause ageing, hyperpigmentation, acneic production, elasticity loss, firmness depletion, lines and wrinkling and other developments of skin conditions such as dermatitis with pH dysfunction or contact with certain substances or elements. However, for the time being, the base solution will be applied to cosmetic beauty, without claims to treat dermal disease.

While brands and formulations have worked to construct novel cosmetics, the stratum corneum presents as the gatekeeperper se. Chemical enhancements have been introduced which improve penetration of products. These penetration enhancers can temporarily or irreversibly ruin the structure of the barrier, allowing for easier entry or diffusion of the solution through the skin. This is highly damaging and irritating to tissue. Moreover, formulations are generally regulated and maintained at a stable pH of 5-5.5 to serve the dermal tissue well. Adjustment of pH using agents such as citric acids or hydroxides can also be highly sensitising and uncomfortable for skin, even in non-sensitive skin typed individuals. This necessitates the need for a more suitable vehicle for the delivery of cosmetics without disrupting the skin's barrier, modifying penetration or pH in a damaging manner, whilst retaining impactful results and restoration of healthy dermal function in any gender, age or skin-concemed individual.

SUMMARY OF THE INVENTION

The present inventors have identified a need to develop an improved cosmetic delivery system with pH buffering capabilities in a non-nefarious manner and improving upon current base dermocosmetic chemical solutions which simply use water which is an inefficient solvent. The chemical compositions of the present invention, which are presented as reconstituable solids and maybe substantially non-aqueous based, act as an improved solvent and is also capable of effectively being formulated directly and applied topically to treat various cosmetic skin conditions (referred herein as "dermal conditioning"), or mixed with additional ingredients, for instance, via emulsion and other techniques (such as sonication) to produce other dermatologically beneficial formulations.

Without wanting to be bound by any particular theory, the present inventors have identified and developed new base compositions to provide novel cosmetics delivery vehicles as the reconstituable compositions described herein contain electrolytes and certain metabolites which are beneficial to the dermal layers. The present compositions and formulations disclosed herein replicate,in part, interstitial fluid, or the fluid which bathes our cells, delivering nutrients and housing active proteins, enzymes and other peptides such as collagen. The reconstituable compostions when formulated and complemented by additional components/ingredients may encourage endogeny, inhibit inflammation and enzyme processes which cause ageing, acneic production, hyperpigmentation and dermal dehydration.

Synthetic peptides are widely employed throughout the skincare industry to downregulate the presence of destructive enzymatic processes and mitigate inflammatory or oxidative response. These actions reverse effects of UV induced skin damage and stimulate endogeny of healing or growth factors. Endogeny refers to organic growth from within and most products feature this common goal in the market today. However, the predominant carrier fluid used in contemporary cosmetics is purified water, which is often not effective; for instance, it is unable to solubilise certain desired ingredients.

Peptides do not have the ability to assimilate effectively or dissolve properly and penetrate the skin within water whereas the cosmetic base and paired solutions will greatly enhance the solubility of peptides, paired ingredients and other skincare components as we have simulated bio-identical cellular fluid. For example, collagen cannot penetrate the skin; instead, it tends to sit on top of the skin as a 'moisturising factor'. The same applies to other developed peptides including Argireline, which is a fragment of the SNAP-25 protein, the substrate of Botox; however, due to its lack of penetrance, it cannot cause muscular relaxation as Botox can. As such, the most effective means of stimulating these factors or delivering said peptides is via invasive cosmetic procedures, where certain substances are injected to reach the interstitial fluid and deeper dermal layers.

The cosmetic base compostions disclosed herein will act as a primary carrier and cosmetic component as this allows peptides and amino acids to dissolve, penetrate and function as intended. This notion also applies to strategic ingredients paired with the cosmetic base used herein to offer clinically validated, innovative and intelligent bio-cellular skincare which will enhance the cosmetics industry. Imperatively, the inventors believe the solution to truly enhance non-invasive dermal regeneration, addressing all areas within the dermal matrix, applying to all ages, genders and dermal concerns with no market sector limitation. Currently, no product remotely resembles the use of replicated interstitial fluid and serves as an immense advantage in navigating through most of the 'noise' within the industry.

The reconstituable cosmetic base compositions disclosed herein may be developed further to offer clinical grade formulations within Dermatology or Cosmetic Procedure Practices. Such expansions may include cosmetic procedural formulations such as a novel 'filler' preparation.

The present invention also contemplates the development of novel cosmetic and dermocosmetics formulations made from such base cosmetic compositions with an acidic buffer capacity to ensure optimal dermal outcomes. Thus, the present invention is predicted, in part, on the understanding that pH control plays a crucial role in healthy skin function conducive towards dermal conditioning and the inventors have developed a series of cosmetic aqueous based solutions which provide effective dermal conditioning properties at a pH of from 3.5 to about 6, preferably between pH 5-5.5.

Accordingly in one aspect the invention provides a reconstitutable cosmetic base composition in the form of a solid mixture comprising:

i) calcium ions and magnesium ions; ii) potassium ions; iii) chloride ions; iv) sodium ions;

and at least 4 or more of the following:

v) polyglutamic acid; vi) polylysine; vii) zinc pyrrolidine carboxylic acid (L-PCA); viii) holo-recombinant human lactoferrin (derived from rice); ix) poly-arginine; x) lecithin; xi) niacinamide; xii) linoleic acid (LA), and/or alpha LA, and/or oleic acid; xiii) beta-sitosterol; xiv) pantothenic acid; xv) D-glucose; xvi) diglycerin and/or glycerin; xvii) talactoferrin; xviii) L-glutamate; xix) L-aspartate; xx) L-glutamine; xxi) thiamine pyrophosphate; xxii) L-camitine; xxiii) beta-glucan; xxiv) phlorizin; xxv) asiatic acid; xxvi) copper ion (catalyst)-Cu2+ source; xxvii) copper tripeptide; xxviii) xanthohumol; xxix) berberine; xxx) Vitamin F; xxxi) N-acetyl Glucosamine; xxxii) Pycnogenol; and xxxiii) Adenosine; and at least one buffer selected from the group consisting of citric acid, succinic acid, L lactic acid, glycolic acid, malic acid, gallic acid, L-mandelic acid, R-mandelic acid, azelaic acid, d-gluconic acid, sebacic acid, adipic acid, and chlorogenic acid; wherein once reconstituted the composition is characterised as having a pH of from about 3.5 to about 6.

In certain embodiments the base composition is reconstituted in a solvent or solvent mixture comprising one or more of ethoxydiglycol, 1,3-butylene glycol, 1,3-propanediol, SD alcohol 40-B, hexyldecanol, dipropylene glycol, 1,2 hexanediol, Birch sap, gluconolactone and water.

In certain embodiments the base composition is reconstituted in a solvent or solvent mixture comprising one or more of ethoxydiglycol, 1,3-butylene glycol, 1,3-propanediol, SD alcohol 40-B, hexyldecanol, dipropylene glycol, 1,2 hexanediol, gluconolactone and Birch sap.

In certain embodiments the base composition is reconstituted in a solvent mixture which is free or substantially free of water.

It will be appreciated that while the preparation of the compositions and formulations described herein may be prepared using quantites of water the end formulated product can be further processed to remove substantially all of water.

In certain embodiments the reconstitutable cosmetic base composition comprises at least or more of v) to xxxiii).

In certain embodiments the reconstitutable cosmetic base composition comprises at least 6 or more of v) to xxxiii).

In certain embodiments the reconstitutable cosmetic base composition comprises at least 7 or more of v) to xxxiii).

In certain embodiments the reconstitutable cosmetic base composition comprises at least 8 or more of v) to xxxiii).

In certain embodiments the reconstitutable cosmetic base composition comprises at least 9 or more of v) to xxxiii).

In certain embodiments the reconstitutable cosmetic base composition comprises at least 11 or more of v) to xxxiii).

In certain embodiments the reconstitutable cosmetic base composition comprises at least 12 or more of v) to xxxiii).

In certain embodiments the reconstitutable cosmetic base composition comprises at least 13 or more of v) to xxxiii).

In certain embodiments the reconstitutable cosmetic base composition comprises at least 14 or more of v) to xxxiii).

In certain embodiments the reconstitutable cosmetic base composition comprises at least 16 or more of v) to xxxiii).

In certain embodiments the reconstitutable cosmetic base composition comprises at least 17 or more of v) to xxxiii).

In certain embodiments the reconstitutable cosmetic base composition comprises at least 18 or more of v) to xxxiii).

In certain embodiments the reconstitutable cosmetic base composition comprises at least 19 or more of v) to xxxiii).

In certain embodiments the reconstitutable cosmetic base composition comprises between 7-15 of v) to xxxiii).

In certain embodiments the reconstitutable cosmetic base composition comprises between 7-14 of v) to xxxiii).

In certain embodiments the reconstitutable cosmetic base composition comprises between 7-13 of v) to xxxiii).

In certain embodiments the reconstitutable cosmetic base composition comprises between 7-12 of v) to xxxiii).

In certain embodiments the reconstitutable cosmetic base composition comprises between 7-11 of v) to xxxiii).

In a further aspect the invention provides a reconstitutable cosmetic base composition in the form of a solid mixture comprising:

i) calcium ions and magnesium ions, preferably at a molar concentration ratio of 5:1 to 1:1, wherein said calcium ions are at a concentration of from 0.1 to 2.5 mmoles/L; ii) from 2.5 to 6.2 mmoles/L potassium ions; iii) from 96 to 126 mmoles/L chloride ions; iv) from 100 to 150 mmoles/L sodium ions;

and at least 4 or more of the following:

v) 20-500 pmoles/L polyglutamic acid; vi) 20-500 pmoles/L polylysine; vii) 10-200 pmoles/L zinc pyrrolidine carboxylic acid (L-PCA); viii) 10-100 pmoles/L holo-recombinant human lactoferrin (derived from rice); ix) 1-200 nmoles/L poly-arginine; x) 10-1000 pmoles/L lecithin xi) 500-1000 pmoles/L niacinamide; xii) 10-100 pmoles/L linoleic acid (LA), and/or alpha LA, and/or oleic acid; xiii) 500-1000 pmoles/L beta-sitosterol; xiv) 500-1000 pmoles/L pantothenic acid; xv) 2-20 mmoles/L D-glucose; xvi) 50-150 pmoles/L diglycerol; xvii) 2-20 pmoles/L talactoferrin; xviii) 150-450 pmoles/L L-glutamate; xix) 2-30pumoles/L L-aspartate; xx) 200-600 pmoles/L L-glutamine; xxi) 10-60 nmoles/L thiamine pyrophosphate; xxii) 10-70 pmoles/L L-carnitine; xxiii) 2-20 moles beta-glucan; xxiv) 2-20 moles phlorizin; xxv) 2-20 moles asiatic acid; xxvi) 2-20 moles copper ion (catalyst)-Cu2+ source; xxvii) 2-20 moles copper tripeptide; xxviii) 2-20 moles xanthohumol; xxix) 2-20 moles berberine; xxx) 2-20 moles Vitamin F; xxxi) 2-20 moles N-acetyl Glucosamine; xxxii) 2-20 moles Pycnogenol; and xxxiii) 2-20 moles Adenosine; and at least one buffer selected from the group consisting of citric acid, succinic acid, L lactic acid, glycolic acid, malic acid, gallic acid, L-mandelic acid, R-mandelic acid, azelaic acid, d-gluconic acid, sebacic acid, adipic acid, and chlorogenic acid; wherein once reconstituted the composition is characterised as having a pH of from about 3.5 to about 6.

In another aspect the invention provides a reconstituted cosmetic base composition comprising:

i) calcium ions and magnesium ions; ii) potassium ions; iii) chloride ions; iv) sodium ions; and at least 4 or more of the following: v) polyglutamic acid; vi) polylysine; vii) zinc pyrrolidine carboxylic acid (L-PCA); viii) holo-recombinant human lactoferrin (derived from rice); ix) poly-arginine; x) lecithin; xi) niacinamide; xii) linoleic acid (LA), and/or alpha LA, and/or oleic acid; xiii) beta-sitosterol; xiv) pantothenic acid; xv) D-glucose; xvi) diglycerin and/or glycerin; xvii) talactoferrin; xviii) L-glutamate; xix) L-aspartate; xx) L-glutamine; xxi) thiamine pyrophosphate; xxii) L-camitine; xxiii) beta-glucan; xxiv) phlorizin; xxv) asiatic acid; xxvi) copper ion (catalyst)-Cu2+ source; xxvii) copper tripeptide; xxviii) xanthohumol; xxix) berberine; xxx) Vitamin F; xxxi) N-acetyl Glucosamine; xxxii) Pycnogenol; and xxxiii) Adenosine; and at least one buffer selected from the group consisting of citric acid, succinic acid, L lactic acid, glycolic acid, malic acid, gallic acid, L-mandelic acid, R-mandelic acid, azelaic acid, sebacic acid, adipic acid, and chlorogenic acid; wherein once reconstituted the composition is characterised as having a pH of from about 3.5 to about 6, and that the composition has been reconstituted in a solvent or solvent mixture comprising one or more of ethoxydiglycol, 1,3-butylene glycol, 1,3-propanediol, SD alcohol 40-B, hexyldecanol, dipropylene glycol, 1,2 hexanediol, gluconolactone, Birch sap, and water.

In a further aspect the invention provides a reconstituted cosmetic base composition comprising:

i) calcium ions and magnesium ions, preferably at a molar concentration ratio of 5:1 to 1:1, wherein said calcium ions are at a concentration of from 0.1 to 2.5 mmoles/L; ii) from 2.5 to 6.2 mmoles/L potassium ions; iii) from 96 to 126 mmoles/L chloride ions; iv) from 100 to 150 mmoles/L sodium ions; and at least 4 or more of the following: v) 20-500 pmoles/L polyglutamic acid; vi) 20-500 pmoles/L polylysine; vii) 10-200 pmoles/L zinc pyrrolidine carboxylic acid (L-PCA); viii) 10-100 pmoles/L holo-recombinant human lactoferrin (derived from rice); ix) 1-200 nmoles/L poly-arginine; x) 10-1000 pmoles/L lecithin; xi) 500-1000 pmoles/L niacinamide; xii) 10-100 pmoles/L linoleic acid (LA), and/or alpha LA, and/or oleic acid; xiii) 500-1000 pmoles/L beta-sitosterol; xiv) 500-1000 pmoles/L pantothenic acid; xv) 2-20 mmoles/L D-glucose; xvi) 50-150 pmoles/L diglycerol; xvii) 2-20 tmoles/L talactoferrin; xviii) 150-450 tmoles/L L-glutamate; xix) 2-30tumoles/L L-aspartate; (xx) 200-600 tmoles/L L-glutamine; (xxi) 10-60 nmoles/L thiamine pyrophosphate; xxiii) 2-20 tmoles beta-glucan; xxiv) 2-20 tmoles phlorizin; xxv) 2-20 tmoles asiatic acid; xxvi) 2-20 tmoles copper ion (catalyst)-Cu2+ source; xxvii) 2-20 tmoles copper tripeptide; xxviii) 2-20 tmoles xanthohumol; xxviv) 2-20 tmoles berberine; xxx) 2-20 moles Vitamin F; xxxi) 2-20 tmoles N-acetyl Glucosamine; xxxii) 2-20 tmoles Pycnogenol; and xxxiii)2-20 tmoles Adenosine; and at least one buffer selected from the group consisting of citric acid, succinic acid, L lactic acid, glycolic acid, malic acid, gallic acid, L-mandelic acid, R-mandelic acid, azelaic acid, sebacic acid, d-gluconic acid, adipic acid, and chlorogenic acid; wherein once reconstituted the composition is characterised as having a pH of from about 3.5 to about 6, and that the composition has been reconstituted in a solvent or solvent mixture comprising one or more of ethoxydiglycol, 1,3-butylene glycol, 1,3-propanediol, SD alcohol 40-B, hexyldecanol, dipropylene glycol, 1,2 hexanediol, gluconolactone, Birch sap, and water.

In certain embodiments, and in respect to anyone of the above aspects, the at least 4 or more ingredients (other than i) to iv)) may selected from the following:

Beta-Glucan

Glycerin

Diglycerin Recombinant Lactoferrin (preferably Rice derived) Niacinamide Pantothenic Acid Linoleic Acid Oleic Acid Vitamin F Lecithin N-acetyl Glucosamine Phlorizin Astaxanthin Asiatic Acid Copper trippedide Copper ion Xanthohumol Pycnogenol Adenosine

In respect to the aforementioned ingredients (other than i) to iv)) in certain embodiments each ingredient (when present) may be independently in any amount (%wt/wt of the total composition/formulation) from about 0.001%-5% wt/wt, such as 0.003, 0.005, 0.01, 0.04, 0.08, 0.10, 0.20, 0.30, 0.50, 0.70, 0.90, 1.1, 1.2, 1.3, 1.5, 1.7, 1.9, 2.0, 2.2, 2.3, 2.5, 2.7, 3.0, 3.3, 3.5, 3.8, 4.0, 4.4, 4.6, 4.8, or about 4.9 or any range in between these two figures.

In respect of the above aspects, in some embodiments, the beta-glucan is present in an amount of 0.1 to 6 %wt/wt of the total composition/formulation, such as 0.20, 0.30, 0.50, 0.70, 0.90, 1.1, 1.2, 1.3, 1.5, 1.7, 1.9, 2.0, 2.2, 2.3, 2.5, 2.7, 3.0, 3.3, 3.5, 3.8, 4.0, 4.4, 4.6, 4.8, 4.9, 5.2, 5.5, 5.7, or about 5.9% or any range in between these two figures.

In some embodiments the buffering agents are present in an amount of 0.1 to 6 %wt/wt of the total composition/formulation, such as 0.20, 0.30, 0.50, 0.70, 0.90, 1.1, 1.2, 1.3, 1.5, 1.7, 1.9, 2.0, 2.2, 2.3, 2.5, 2.7, 3.0, 3.3, 3.5, 3.8, 4.0, 4.4, 4.6, 4.8, 4.9, 5.2, 5.5, 5.7, or about 5.9% or any range in between these two figures.

In some embodiments the solvent or solvent mixture is present in an amount of about 30 to 80% (%wt/wt of the total composition/formulation), such as about 35, 40, 45, 50, 55, , 65, 70, 75% or any range in between these two figures.

In an embodiment the composition is for use in dermal conditioning of a subject.

In an embodiment the dermal conditioning is skin moisturising.

In an embodiment the dermal condition is dry skin.

In an embodiment the dermal conditioning is ageing.

In an embodiment the dermal conditioning is skin hyperpigmentation.

In an embodiment the dermal conditioning is skin-brightening.

In an embodiment the dermal conditioning is acneic production.

In another aspect the invention provides a cosmetic formulation comprising the reconstituted composition and one or more of the following: emulsifying agent, sunscreen agent, stabilising agent, dispersing agent, suspending agent, thickening agent, or colouring agent.

In an embodiment the invention provides reconstituable cosmetic compositions and cosmetic formulations which are non-inorganic-phosphate-buffered, that is to say that they do not contain an inorganic phosphate buffer.

In certain embodiments the cosmetic base compostion or formulation preferably comprises calcium ions and magnesium ions at a concentration ratio of from 4:1 to 2:1, more preferably about 3:1.

Preferably, the cosmetic base composition or formulation of the invention comprise from 0.1 to 2.5 mmoles/L calcium ions and/or from 0.4 to 2.5 mmoles/L magnesium ions.

In one embodiment, the cosmetic base composition or formulation comprise calcium ions at a concentration of from 1.0 to 2.5 mmoles/L, preferably from 1.1 to 1.4 mmoles/L, more preferably from 1.2 to 1.3 mmoles/L, even more preferably about 1.25 mmoles/L.

The cosmetic base compositions of the invention or formulations, preferably comprise magnesium ions at a concentration of from 0.2 to 0.6 mmoles/L, more preferably from 0.3 to 0.5 mmoles/L, even more preferably about 0.45 mmoles/L magnesium ions.

In one embodiment, calcium and magnesium ions are present at a concentration of about 1.25 mmoles/L and about 0.45 mmoles/L respectively.

In certain embodiments, the cosmetic base compositions or formulations may also comprise amounts of hydrogen carbonate ions, for instance, hydrogen carbonate ions may be present at a concentration of from 21 to 35 mmoles/L, or at a concentration of from 22 to 29 mmoles/L, or at a concentration of about 25 mmoles/L.

In one embodiment, the cosmetic base compositions of the invention or formulations are topically applied to the skin directly or may be impregnated into a dressing which is subsequently applied to the skin.

Accordingly, in a further aspect the present invention provides dressings impregnated with the cosmetic base compositions of the invention or formulations disclosed herein.

In addition to the above, the invention also encompasses concentrated forms of the reconstituted compositions defined herein. For example, 1 to 50x, preferably 5 to 20x concentrates are encompassed. In order to produce a concentrate of 1x, that is to say working strength, concentration, 5x, lOx, 20x and 50x concentrates require, respectively, 4, 9, 19 and 49 volumes of the water to be added to one volume of concentrate.

In another aspect, the invention provides methods of treating a skin condition cosmetically including the step of applying to the skin a reconstituted cosmetic base composition as defined herein or a cosmetic formulation which comprises said reconstituted cosmetic base composition.

In another aspect, the invention provides methods of dermal conditioning including the step of topically applying to the skin a reconstituted cosmetic base composition as defined herein or a cosmetic formulation which comprises said reconstituted cosmetic base composition.

In a further aspect, the invention provides methods of reducing inflammation associated with a mild skin abrasion or skin redness including the step of topically applying to the skin a reconstituted cosmetic base composition as defined herein or a cosmetic formulation which comprises said reconstituted cosmetic base composition.

The invention also encompasses the use of a reconstitutable or reconstituted cosmetic base composition as defined herein for the manufacture of a cosmetic formulation for dermal conditioning.

In yet a further aspect, the invention encompasses uses of the cosmetic dermal compositions and formulations of the invention for topically delivering additional nutrients or agents (e.g., synergistic or supra additive agent) to the skin of a subject, for example an anti-inflammatory agent, such as at least one stem cell, synthetically derived small-molecule, peptide or genomic derived protein, or amino acid, anti-oxidant agent or hydroxy acids in the alpha, beta, poly and lipo classes (AHA, BHA, PHA, LHA), fermented microbiomic enhancement agents and dermal soothing agents.

In preferred embodiments, the delivery is effected by topical administration.

In certain embodiments of the above methods, the cosmetic compositions or formulations is applied to the skin and maintained at a temperature of between 4 and 40°C (eg 4 to 38C) such that the surface of the skin is maintained in a suitable state and products remain stable as per cosmetic regulatory standards.

DETAILED DESCRIPTION OF INVENTION

The term "dermal conditioning" refers to the normalisation of the skin tissue after having a cosmetic condition requiring treatment or for cosmetic purposes. Such conditions includes birthmarks, botox injections or filler preparation due to extrinsic ageing concerns, acne scarring, stretch marks, , dry skin, inflammation, hyperpigmentation, acneic production, ageing and other aesthetic features such as radiance.

Some of the advantages of the present inventive compositions and formulations include:

Encouragement of dermal healing and restoration of integrity via regulation of micro-circulation between dermal cells and connective tissue during metabolic action and promotion of epidermal cell growth.

• Regeneration of elasticity via epidermal re-uptake - with 20% more epidermal water re-uptake with beta-glucan compared to hyaluronic acid.

• Regulates sebum and oil production, anti-acneic and anti-congestive properties and suppression of comedone formation via downregulation of 5alpha reductase enzyme.

• Further acneic regulation via stagnation of lipid peroxidation, anti-inflammatory activity and antimicrobial/antibacterial properties.

• Stimulation of endogenous glycosaminoglycans, peptides and hyaluronic acid. Prevents denaturation and depletion of macromolecules.

• Hydration and moisturisation throughout all levels of dermal matrix.

• Synthesis of endo-peptides such as various types of collagen.

• Mitigates post-inflammatory hyperpigmentation via transfer cycle of melanosomes from melanocytes into keratinocytes. Generalised brightening activity, without containing skin-bleaching agents such as hydroquinone.

• Regulation of micro-circulation between dermal cells and connective tissue during metabolic action.

• Strengthening and reinforcement of skin's acid mantle, barrier function and microbiomic function.

• Anti-aging qualities through promotion of growth factors and other complementary molecules including elastin, filaggrin, involucrin, fibrillin etc. and denaturation or suppression of MMP activity. Also promotes fibroblast proliferation.

• Potent anti-inflammatory action, suppressing the TNF-alpha, NF-kb and other pathways, and reducing the release of inflammatory factors such as ILs and PEGs. Attenuated phosphorylation induced upstream of cytokines and inhibits tyrosinases, TRP 1 and TRP 2 and limits protein kinase A via inhibition of cyclic adenosine monophosphate.

• Calming and soothing action against irritated skin due to various aggressors or compromised skin condition

• Reversal of irradiation in dermal cells via exposure to UV light - restores and reverses prior photodamage at the cellular level whilst offering photoprotective properties

• Significant antioxidation ability and suppresses ROS, lipid peroxidation and other free radicals. Multiple scavenger agents of free radicals.

• Humectant properties which draw water to the upper levels of the skin from the environment, emollience as well as occlusive properties of the moisturiser to seal in dermal conditioning treatments via product use.

• Prevention of barrier damage and exposure to external aggressors due to an invisible film forming over the barrier, which in turn, significantly decreased trans epidermal water loss.

• Increases skin cell turnover rate at the same level, if not more than retinol, without irritation/skin sensitivity or increased photosensitivity associated, maintaining anti-aging effect.

• Upregulation of Aquaporin 3 gene which hydrates skin.

• Improves synthesis of ceramides, free fatty acids and cholesterol within skin. Methods such as sonication and micro-emulsion may also be utilised to assist with delivery of these components within a product formulation.

• Multiple exfoliation type properties through various hydroxy acid mechanisms - 'melting' mechanism of AHAs, 'excavating' mechanism of BHAs, keratolytic and 'lifting' action of PHAs and LHAs. Impregnated exfoliation pads to have combination of all 4 acid types, suitable for the very sensitive or compromised skin types.

• DNA repair and proteasome cleansing activity. Other anti-inflammatory and many anti-aging based exogenously applied peptide action. Promotes cell communication and signalling and neuropeptide-based actions.

• Increases thickness of epidermis and increases expression of cytokeratins 5 and 6.

Dermal conditioning is a complex process which is characterised by intercalating degradation and re-assembly of connective tissue and epidermal layer and will largely depend on the condition which has caused the skin to be preforming non-optimally. The pH value influences indirectly and directly all biochemical reactions taking place within and on the skin.

Many of these factors occur at a microscopic level and therefore can be referred to as the microenvironment. Inside this microenvironment, factors are at play that influence whether the dermal condition can be ameliorated or becomes chronically stalled.

The microenvironment is critical to treating a cosmetic dermal condition. For example, elements inside the microenvironment determine whether the condition becomes mitigated versus expressed or dysfunctional. Those same elements determine whether proteases (i.e. MMPs) create prolonged inflammation and therefore delay skin normalisation and further the degradation of integral dermal proteins to maintain suppleness, firmness, elasticity and regulation of fine line/wrinkling.

It has been proven that the surface pH of a skin plays an important role in skin conditioning as it helps control infection and increase antimicrobial activity, oxygen release, angiogenesis, protease activity, and bacterial toxicity. Therefore, the pH value of the skin affects the regular cellular events.

The present inventors understand that the process of cosmetically treating skin conditions needs to take place in a suitable microenvironment, which is influenced by different intrinsic and extrinsic factors. Among these intrinsic factors is the pH, on which depend essential functions such as:

• the release of oxygen.

• angiogenesis- this is important to repair the capillary bed and allow normalisation of the skin.

• protease activity.

• bacterial toxicity.

Lowering pH below 7 slows down enzyme activity of proteases such as elastase, plasmin, cathepsin G and MMP-2 (see Figure 1 on end page).

The term "subject" or "subjects" encompasses, where appropriate, human subjects and non-human animal subjects, for example mammalian subjects such as rodents, pigs, monkeys, dogs and the like as appropriate in experimental research and cattle, horses and the like as occurs in veterinary practice.

The compositions and formulations disclosed herein may be utilised in the following products:

Serum - inclusive of all agents which address embodiments related to dermal conditioning above, suitable for all skin types, all skin concerns and featuring deep sea marine bacterium with innovative filtration, proanthocyanidin agents, significant antioxidants and age defying components which reinforce cellular and mitochondrial integrity.

Moisturiser- will include a blend of 4 super oil compounds to create a micro-emulsion, predominantly focusing on restoration of the lipid component of the bilayer and utilising innovative techniques, such as sonication, to improve and increase endogenous ceramide and lipid synthesis within the dermal tissue.

Essence (this may include a blend of ferments like galactomyces or mugwort etc.). Essences promote the absorption of products to follow, through skin dampening and relative activity of the stratum corneum, and offers non-viscous, easily absorbed and highly beneficial dermal conditioning components as a first step following a cleanse.

Cleanser- simple hydrating formulation without stripping the skin, and may also contain yerba mate, and centella water etc. Cream cleanser preferably or innovative surfactant technology without stripping the skin.

Pre-soaked exfoliant pads with innovative 'time release technology' - pH buffering provides a very unique edge over other pads due to pH of acids and the present solutions ability to buffer up which separates active components of the exfoliants. The pad may feature unique acids such as PHAs and LHAs suitable for daily use or sensitive skin types. In some embodiments BHAs (eg salicylic acid) can be excluded as they do not conform to this time release mechanism. The pad may also be embedded with pore flushing marine extracts in place of a BHA, unless otherwise specified. The pad may also include anti microbial AHA.

Hydrogel mask covering face and neck with strategically placed micro-darts to painlessly penetrate the upper layer of the skin. This is being used in small colloidal patches for acne and pimples, however we will release a complete micro-dart mask for the entire face (darts to be inserted around areas of concern like outer comers of eyes, corners of mouth, forehead/upper brow etc. - where botox would be placed essentially) that features a hyper-peptide complex of many classes of exogenous dermal peptides. Argireline (derivative of botox protein substrate) will be the featured peptide here as micro-darts and the use of VR will assist with clinical or injectable results, at home.

Cosmetic Formulations comprising the Cosmetic Compositions disclosed herein

The invention contemplates topical formulations may be in the form of solid, gel or liquid formulations which utilise the cosmetic based compositions as the main cosmetic carrier material.

Liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilising agents, and the like.

In some embodiments the compositions of the present invention include Birch sap, also known as Birch water or Birch juice or, as a concentrated form "Birch syrup".

For topical administration to the epidermis the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.

Chloride ions are preferably provided as sodium, potassium, calcium and magnesium salts.

Compositions encompassed by the present invention comprise a number of substrates which retain metabolic homeostasis of tissues and organs. Glucose and diglycerol have been shown to be satisfactory in meeting the energy demands of isolated tissues. Apart from their ability to be metabolized, diglycerol and glucose also have free radical scavenging and membrane stabilizing properties, which have been shown to be extremely important in maintaining the physiological viability of tissues and organs.

As described above, aspartate and glutamate can also be included in the solutions according to the invention, to enhance oxidative metabolism by replenishing tricarboxylic acid (TCA) cycle intermediates, thereby maintaining high energy phosphate levels even during ischemic insult. Similarly, glutamate is involved in maintaining intracellular oxidation-reduction potentials. It is envisaged that by optimizing the aspartate-malate and glycerol phosphate shuttles, cells will maintain an optimal NAD/NADH (nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide) balance and thereby sustain adenine nucleotide levels. In addition, glutamate and glutamine can act as intermediary metabolites to form pyroglutamate and thereafter participate in the gamma glutamyl cycle to synthesise glutathione, a beneficial agent in preventing the generation of toxic oxygen radicals associated with the incidence of reperfusion injury in mammalian tissues and organs during storage of donor organs prior to transplantation and following blood volume replacement therapies.

Thiamine plays an important role in the oxidation of a-keto acids (by the action of thiamine cocarboxylase) and prevents the accumulation of pyruvate and toxic pyruvate aldehyde, thereby minimizing cellular apoptosis and accompanying necrosis of tissues and associated organs.

In the TCA cycle, thiamine pyrophosphate (TPP), which is included in preferred solutions of the invention, is a co-factor in the metabolism of a-ketoglutaric acid to form succinyl coenzyme A, by oxidative decarboxylation, or to form glutamate, by reductive amination. In essence, TPP is involved in numerous interrelated biochemical pathways, especially those of the Pentose Phosphate and Glycolytic pathways. In the context of the present invention, thiamine pyrophosphate (TPP), plays an essential role in optimising the efficacy of the RBC's, during vascularisation of the dermal cytoarchitecture, by generating ATP via the enzyme, transketolase, as RBC's are devoid of mitochondria..

Further, the inclusion of thiamine pyrophosphate in the formulation of the compositions of the invention would also appear to be of necessity to peritoneal dialysis patients in order to prevent phosphate ion depletion and calcification as it is readily dialyzable across hemodialysis membranes (MW-175 Dalton) and has been previously administered either intravenously or via the hemodialysis or peritoneal dialysis solution to replenish plasma phosphate and/or pyrophosphate levels. The thiamine may be employed as thiamine pyrophosphate, thiamine diphosphate or thiamine diamide. Preferably the solutions of the invention comprise thiamine as thiamine pyrophosphate chloride.

The vitaminoid camitine has been reported to have multiple effects in improving cardiac function other than by simply optimizing oxidative metabolism, such as, by promoting the utilization of alternative substrates and may additionally improve coronary blood flow. L-camitine is preferred to the D- or DL isomers because it causes no inhibition of acetyl co-enzyme A/free fatty acid metabolism. Preferably the vitaminoid component comprises 50 moles/L of [-]--hydroxy-y-trimethylamino-butyrate hydrochloride (L carnitine). In this invention, the preferred inclusion of the L-isomer of carnitine is intended to optimise the transport of long chain fatty acids from the cytosol into the mitochondrial matrix to the site of p-oxidation and thereby to buffer the intramitochondrial acetyl CoA/CoA ratio (where CoA is Coenzyme A) by stimulating the synthesis of acetyl camitine from carnitine acetyl transferase. This reduction in the ratio of acetyl CoA/CoA will result in an efflux of acetyl camitine from the mitochondria with an associated stimulation of pyruvate dehydrogenase and reversal of fatty acid inhibition of glucose oxidation. Ultimately the optimization of free fatty acid utilization as an energy source is essential for all types of cells but this must be done with preservation of carbohydrate (glucose) utilization by optimized functioning of the enzymes involved in glycolysis, e.g. hexokinase, glucokinase, phosphofructokinase.

As described above, solutions of the invention may also comprise insulin. The use of human recombinant insulin (e.g. expressed in E. coli or S. cerevisiae) not only precludes the risk of antigenic or viral contamination in recipient skin, as may be the case with insulin derived from other mammalian or animal sources, but also leads to a better fit being achieved of insulin molecules to human insulin receptor structure, i.e. Receptor specificity will be optimized to retain the many associated functions of insulin in cellular processes.

Essentially, the biological effects of insulin do not simply relate to its ability to regulate carbohydrate metabolism and facilitated transport of circulating glucose into cells but also in its ability to bring about (i) the enhancement of intracellular glucokinase activity and amino-acid incorporation into protein, (ii) stimulation of DNA (deoxyribose nucleic acid) translation into proteins, (iii) increased lipid synthesis and (iv) stimulation of sodium, potassium and inorganic phosphate transport across cell membranes.

The concentrations of ionic species in solution according to the invention acknowledge the activity coefficients of each ionic species and not simply their total serum concentrations. For example, serum binding of calcium and magnesium ions must be distinguished from the actual free, ionized levels of these ions. Magnesium ions are important in a number of critical cellular reactions and their extracellular presence is reported to stimulate mitochondrial respiratory activity and modulate the effects of rapid calcium influx and potassium efflux. Equally, an adequate concentration of calcium ions is important to maintain the free levels of this ion present in the circulation.

The ionic conductivity of the solutions of the invention is preferably comparable to that of human serum, namely 12.00.3 mS cm' and as such maintains the ionized status of the cell membrane and activities of enzymic moieties.

Thus in accordance with the above, the compositions of the present invention are isosmotic to human serum (ca. 290 mOsmoles/L) and do not appear to necessitate the inclusion of plasma expanders, as demonstrated by the fact that only minor changes (ca. 8%) in hydration occur during long term (i.e. 4 to 52 hr) hypothermic perfusion of the isolated rat heart and visceral nerve-muscle preparations. This may be explained by the fact that the cell membrane lies in continuity with a 99% gel interstitial phase so providing natural colloidal buffering to excess Donnan ionic equilibrium exchange across the cell membrane. The majority of the osmotic pressure is provided by sodium ions and their accompanying anions, and only a small component (ca. 0.5%) can be attributed to plasma proteins. The inclusion of serum levels of the metabolite, glycerol, in this solution may also contribute to osmotic buffering at the dermal interface.

The practicality of including oncotic agents is further compromised by their affinity for calcium and magnesium ions, necessitating prior dialysis in fresh solution so as not to disturb cationic composition. The labile nature of polypeptide expanders also makes them impractical through their predisposition to mechanical denaturation.

The invention envisages that specific sub-components of the solutions of the invention can be used individually or in any combination.

Particular embodiments of the invention are described below by way of the following examples. The examples are provided to illustrate embodiments of the invention but are not to be considered as limiting in any way.

Example 1

Formulation Examples

Component Comparator 1 (mmol/L) 2 (mmol/L)

(mmol/L)

Sodium Ions 135 138 135

Potassium Ions 5 5 5

Calcium Ions 1.25 1.25 1.25 Magnesium Ions 0.45 0.45 0.45

Bicarbonate ions 25 0 14 Thiamine 40 None None Pyrophosphate nmol/L L-Carnitine 50 50 50 Hydrochloride ptmol/L ptmol/L pmol/L pH- comparator; 7.3, Ex 1; 3.7 and Ex 2; 5.0.

Example 2 (without buffer)

0041#M conc Gr~q 5s*ppao prce 1pak G/( pirt/betI

R4iecotnbiant Lactofonrim P.wur# vtclf.*j 05 005 7811 84 Is11 t44(fni0 25 [14hOI04 0or9 OW) PanmottlenK acod 0101 0.05 ~a

[W 19*0/Sig 39 0.00198

[51,C2301 ODML 1 0 0*73 00673 &Ii OILA 30 om 6.0 3 40 3 1Ipurchem [4 / so 0132 0316b Se~o~f6006 0 Si53 [5 150 1 12 0 02134, Ntlai 1 0A [5dij EN15041 10.18 0,0514 ;pcWrolido newborjIaidff-CA)I 01 000 £o3 70/1015 031 010015S 0 0=m) [ 140 50n,% 1800 1 Sadervd efn S 0.25 [110/10( 120 03 II N*ACCW cfucosamlne 3 cis1 I A~a [4l1*so 1 15 0.996 01494 Sdum chloract I3 L 4 0.0A £125#l~ 1096 0.0545 allr 506 003 litcl fisa/s00m 128 0.768 -4*o i i* 02 1 AacM f11/0 I11*i8lt 0 006 @1- lo 1 Doz [0bvvf 401250Mg 140 01

221 112 £3101 so 642 a.06025 4462

Example 3 (without buffer) Reagent _____________ COMt G Supplw pnc / pack t/G PVce/bot~i RetombmaMtLscito~ertin trnecalue eust'w) 0.5 0.025 S~- (94718 541 2111s, ______________________ 5 0215 1S~i.A 11440151 04$2 al013 Pantow. cd 101 10 S [%- 193015 4 20196 O9 1~"@ 10- IlM". ( " /1 3o 14 0.11 acid S @2S MMsIFJ 120/1 0.02 moos5 BI 1 10CS .~ [0 /,4 60 1 40 8~a~~m 61/O~g21 036 _________________ 006 00SS s". is W/54 112 v202134

________________________ 1 0 S * 504, 5141 5ft1 102 004514

ZicPyrrolidon caboo KacidL-CAI 0.1 0005 Aienrio [30 /lag 037 0.0018s 0-05 OM~S SW"a [140/50mg 2500 1 Sij-t,5r 135~n- 0£ .XE120/bMg 1,2 0.3 84J~j 115OI&'MeI i A Asev [4nv0/5 0,996 0.1494 Sdu hoie1 0 5snia £27A0/ZSg 11096 00545 pimi,0.13 0006 stit t64 /50m 12" us 768 04 1055 A Aaea [11*/l10 11's 00069 2 co____________ion__ 0.1 OS~ (artiwo tA / £0 S0mg 160 08 _________________________ 23 0.012.5 R~i,ramct LM09/25MgW 536 10,4S _____________________ a_ is5 0.012 IV32.20/59 6.42 0.06025 r44 4 6U

Example 4 (without buffer)

pwftun tclrrin teknpeIteemww) 0.3 0 02S 11,ma 1847) I& 847 11175 ____________________ 5 025 SgmA 114 60 /3" 0192 0073

ar!!thcnicacid 001 Oom 5.gma 119 w " g I13% 00019 inoieK cid 1 0.04 S6ma E341 IN 14 0 17 irhan-~.< kid 1 0.0 U"gm t2".4 s0o* 1 m1 Ii-A I 0.05 Swn f1We?/S 40 ,4 Uv!IG 3 I kkovdwi 14.I VJ 0,122 0144l 6eta toen~ 0336 0.003 Sga f1360D/ SG 712 002136 1OTjmi m.0 SigMA 0141 U)Og 1,028 00314 Vmpwqyrcotdoww aciad ItA) 0.1 0I LI a70)/l10 0-17 000185s "nn0osR 00025 $Sna 1140SP- 21100 7 derve leiim25 VWR f1201 W 32 0,3

____________________ 1hctd 0.05 Sms W240 256 1094 0054w _____________________ I Oil 0.006 %441 k (644/ S00 128 07M4 "n________________ 0.1 0015 A Ajta, 17at lot 1711 0000 Cpoon0.1 0.05 CAimyrIl'. IV I ISOMS 160 010 _________________________ a. 0125_ F0vct~ 120)Sv 834r a 1041. ____________________ @23 0125 V*Q to/ so 4.42 000525 r41101194

Example 5 (without buffer)

W.Kiacmamdt S 0.2S 14 60 / 9 0 292 0,073 PartMOwnimc am O 0.03m in00 1 14S 396 0.001U fla#neF 1 0.05, f$ @31830/ 1001" 0373 0*9.71 0.0 100 f1 I i 60 1 053 Ioir~cwm 411.00 0111 04 11,obfI0.05 0.0"3 13560/56 )712 01)Z

ZicynOhdone wbcyacidL.CA1 0.1 ODDS5 jkMO 1370 1 ic 0371 00018S3 _____________________ D .05 0302 1S3141SWO 1,021 01002S7 So ervdteih 0.25s1120/1 H05 1,2 0,3 3K~iKUCn~ 0,15 3 Asear 1499.0o w 0.99 01494 _____________________ choie 00%5 f2 740/5 109I' 0,0549 ____________________ 0.12 0.0" hSeic f64/ 129." U 0769. Men_________________ 0.1 0!00% !,MAear 1 8./let LIS 0.0089 Copn0.1 OOD f40/ ISO- 160 0s Urfe0.23 0.0123 "'IG)SMOq $ 642 009awls F 76I9.1

Example 6 (with buffer) Test sample Mass required (g)

Sodium chloride 0.025 Potassium chloride 1.8637 Calcium chloride dihydrate 0.9188 Magnesium chloride hexahydrate 0.4575 L-Carnitine inner salt 0.0403 D-Glucose 9.9085 L-Aspartic acid 0.0133 L-Glutamic acid 0.2207 L-Glutamine 0.2923 N-acetyl glucosamine 0.45 Water 400g Top up to 500g to achieve 20% of Glycerol solution Azaleic acid 15mg (0.5%) Sitosterol 1.8mg (0.06%) polyglutamic acid 15mg (0.5%) pH 4.31

Example 7 Test sample Mass required (g)

Sodium chloride 0.025 Potassium chloride 1.8637 Calcium chloride dihydrate 0.9188 Magnesium chloride hexahydrate 0.4575 L-Carnitine inner salt 0.0403 D-Glucose 9.9085 L-Aspartic acid 0.0133 L-Glutamic acid 0.2207 L-Glutamine 0.2923 N-acetyl glucosamine 0.45 Water 400g Top up to 500g to achieve 20% of Glycerol solution

Niacinamide 5 Pantothenic acid* 0.01 Linoleic Acid 0 Oleic acid 0 Alpha linolenic acid 0 B1,3 glucan 1 glycerin 58 Beta-Sitosterol 0 Polylysine 0.05 Polyglutamic acid 0 Zinc pyrrolidone carboxyl acid (Zn-PCA) 0.1 Soy derived lecithin 0 N-acetyl glucosamine 0 Phlorizin 0.12 Copper ion 0.1 H20

Solution preparation Dissolve in following order in water 1) Niacinamide 2) Phlorizin 3) Cu2+ 4) Polylysine, Zinc PCA, Pantothenic acid ) Complete to 5g with Glycerin

Example 8

Test sample Mass required (g)

Niacinamide 5 Pantothenic acid* 0.01 Linoleic Acid 1 Oleic acid 1 Alpha linolenic acid 1 Beta 1,3 glucan 1 glycerin 58 Beta-Sitosterol 0 Polylysine 0.05 Polyglutamic acid 0 Zinc pyrrolidone carboxyl acid (Zn-PCA) 0.1 Soy derived lecithin 0 N-acetyl glucosamine 0 Phlorizin 0.12 Copper ion 0.1

Example 9

Reagent Con G r@q Supplier price/pak £/G prie/hottie Pycrognov_ _ 5 0.25 2.3 0.575 Niacinamide 5 0.25 Sigma £14.60 50g 292 0.073 Pantothenlcacid 00 0000 Sigma £19.80/5g 00198 Vitamine F* 0.05 1 0. Sigma £87.30/jO0mL 0.671 0=73 B1,3 glucan 1 0.05 £300/ g 60 3 g|ycerin 60 3 Flourochem £61/ 50g 0.122 0,365 Betaisteml D.06 0.003 Sigma £3O/SG 712 0.02136 Polyglutarnicacid 1 0.05 Sigma £514/j50g 1028 0-0514 Zinc pyrrolidone carboxyl acid (L-PCA) 0.1 0.005 Alexm £3.70 /Og 0.37 000185 Polyvysine 0.05 0.0025 Sigma £514 I 5OOg 1028 0.00257 Soyderived lecithin 5 0.25 VWR £120/100g 1.2 0.3 NWacetyl gjucosamine 3 .15 A Asear £49.80!/3g 0.996 0.1494 Sodiurmchloride 1 0.S Sigma £2740/25# 1096 0.0548 Phlorizin* 0.12 0.006 Selleck E64/ 00mg 128 0768 Adenosine 0.1 0.005 AAsear £17.8/1Gg 1.78 0.089 Copper ion 01 0.00S Carbasyntd- £40 / 250mg 160 0.8 gerberine 0.25 0.0125 VWR £32.10/Sg 6.42 0.08025

The following factors should be taken into account when preparing the compositions (if applicable):

1) The method of assembly of the solutions and, specifically;

2) Use of solvent as specified above to make up all stock solutions and the 10 times concentrate bottles of manufactured solutions according to the invention;

3) The methods of preparing sterile stock solutions according to the invention and concentrates should not involve autoclaving or gamma-irradiation. For example, irradiation of the solution to achieve sterility will result in degradation of glutamine, glucose, and thiamine pyrophosphate components (if added);

4) The use of glass bottles for storage of all 10 times stock concentrate solutions;

) Preparation of solubilised insulin by acidification at pH 2.4 plus storing insulin ingredients and stock solutions at -20°C.;

6) Preparation of thiamine pyrophosphate plus TPP stock solutions stored at -20°C. under dark conditions (see reason below);

7) Use of magnesium chloride hexahydrate (i.e. 6H20). This is because if the dehydrate salt is used then it adsorbs water so the weight used to calculate the precise magnesium ion content will be in error--this is a common reason for wrongly made up Krebs solutions in terms of correct magnesium ion and calcium ion levels.

The inclusion of all preferred components, as described in this Example, allows these components to work in synergy to produce an overall balanced physiological effect.

Manufacturing Specifications

1) Stock solutions: Various stock concentrations of solutions according to the invention namely, 1x, lOx and 20x for long-term storage have been prepared, but the preferred stock concentrates are 1Ox concentrates using purified water sterile filtered into sealed 100 mL bottles for storage under dark conditions at 3 to 8°C. Stock solutions are reconstituted for use as 1x solutions by the addition of 100 mL oflOx concentrates of stock solutions to 900 mL of purified water with the addition of 2.1 g of sodium hydrogen carbonate to give a final pH of 7.220.04 at 2 0 °C. Sterile stock lOx concentrations of solutions according to the invention have a pH of 4.6+0.2 and have been shown to remain sterile, and free of precipitations, for periods of up to ten years. The recommended manufactured shelf-life of 1Ox stock concentrates of solutions according to the invention is 24 months when stored at 3 to 8°C. under dark conditions.

2) Cocarboxylase: Stock solutions of thiamine pyrophosphate chloride (cocarboxylase) are prepared at 18.4 g/mL using endotoxin-free purified water, sterile filtered into dark sealed vials to prevent the photon degradation of thiamine pyrophosphate, and stored frozen prior to the assemblage oflOx stock concentrates of solutions according to the invention.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A reconstitutable cosmetic base composition in the form of a solid mixture comprising: i) calcium ions and magnesium ions; ii) potassium ions; iii) chloride ions; iv) sodium ions;

and at least 4 or more of the following:

2. A composition according to claim 1 which is reconstituted in a solvent or solvent mixture comprising one or more of ethoxydiglycol, 1,3-butylene glycol, 1,3-propanediol, SD alcohol 40-B, hexyldecanol, dipropylene glycol, 1,2 hexanediol, Birch sap, gluconolactone and water.

3. A composition according to claim 1 which is reconstituted in a solvent or solvent mixture comprising one or more of ethoxydiglycol, 1,3-butylene glycol, 1,3-propanediol, SD alcohol 40-B, hexyldecanol, dipropylene glycol, 1,2 hexanediol, gluconolactone and Birch sap.

4. A composition according to claim 1 which is reconstituted in a solvent mixture which is free or substantially free of water.

5. A composition according to anyone of claims 1 to 4 wherein the reconstitutable cosmetic base composition comprises at least 5 or 6 or more of v) to xxxiii).

6. A composition according to anyone of claims 1 to 4 wherein the reconstitutable cosmetic base composition comprises at least 8 or 9 or more of v) to xxxiii).

7. A composition according to anyone of claims 1 to 4 wherein reconstitutable cosmetic base composition comprises at least 10 or more of v) to xxxiii).

8. A composition according to anyone of claims 1 to 4 wherein the reconstitutable cosmetic base composition comprises at least 11 or more of v) to xxxiii).

9. A composition according to anyone of claims 1 to 4 wherein the reconstitutable cosmetic base composition comprises at least 12 or more of v) to xxxiii).

10. A composition according to anyone of claims 1 to 4 wherein the reconstitutable cosmetic base composition comprises at least 13 or more of v) to xxxiii).

11. A composition according to anyone of claims 1 to 4 wherein the reconstitutable cosmetic base composition comprises at least 14 or more of v) to xxxiii).

12. A composition according to anyone of claims 1 to 4 wherein the reconstitutable cosmetic base composition comprises at least 15 or more of v) to xxxiii).

13. A composition according to anyone of claims 1 to 4 wherein the reconstitutable cosmetic base composition comprises at least 16 or more of v) to xxxiii).

14. A composition according to anyone of claims 1 to 4 wherein the reconstitutable cosmetic base composition comprises at least 17 or more of v) to xxxiii).

15. A composition according to anyone of claims 1 to 4 wherein the reconstitutable cosmetic base composition comprises at least 18 or more of v) to xxxiii).

16. A composition according to anyone of claims 1 to 4 wherein the reconstitutable cosmetic base composition comprises at least 19 or more of v) to xxxiii).

17. A composition according to anyone of claims 1 to 4 wherein the reconstitutable cosmetic base composition comprises between 7-15 of v) to xxxiii).

18. A composition according to anyone of claims 1 to 4 wherein the reconstitutable cosmetic base composition comprises between 7-14 of v) to xxxiii).

19. A composition according to anyone of claims 1 to 4 wherein the reconstitutable cosmetic base composition comprises between 7-13 of v) to xxxiii).

20. A composition according to anyone of claims 1 to 4 wherein the reconstitutable cosmetic base composition comprises between 7-12 of v) to xxxiii).

21. A composition according to anyone of claims 1 to 4 wherein the reconstitutable cosmetic base composition comprises between 7-11 of v) to xxxiii).

22. A reconstitutable cosmetic base composition in the form of a solid mixture comprising:

i) calcium ions and magnesium ions, preferably at a molar concentration ratio of 5:1 to 1:1, wherein said calcium ions are at a concentration of from 0.1 to 2.5 mmoles/L; ii) from 2.5 to 6.2 mmoles/L potassium ions; iii) from 96 to 126 mmoles/L chloride ions; iv) from 100 to 150 mmoles/L sodium ions; and at least 4 or more of the following: v) 20-500 pmoles/L polyglutamic acid; vi) 20-500 pmoles/L polylysine; vii) 10-200 pmoles/L zinc pyrrolidine carboxylic acid (L-PCA); viii) 10-100 pmoles/L holo-recombinant human lactoferrin (derived from rice); ix) 1-200 nmoles/L poly-arginine; x) 10-1000 pmoles/L lecithin xi) 500-1000 pmoles/L niacinamide; xii) 10-100 pmoles/L linoleic acid (LA), and/or alpha LA, and/or oleic acid; xiii) 500-1000 pmoles/L beta-sitosterol; xiv) 500-1000 pmoles/L pantothenic acid; xv) 2-20 mmoles/L D-glucose; xvi) 50-150 pmoles/L diglycerol; xvii) 2-20 pmoles/L talactoferrin; xviii) 150-450 pmoles/L L-glutamate; xix) 2-30pumoles/L L-aspartate; xx) 200-600 pmoles/L L-glutamine; xxi) 10-60 nmoles/L thiamine pyrophosphate; xxii) 10-70 pmoles/L L-carnitine; xxiii) 2-20 moles beta-glucan; xxiv) 2-20 moles phlorizin; xxv) 2-20 moles asiatic acid; xxvi) 2-20 moles copper ion (catalyst)-Cu2+ source; xxvii) 2-20 moles copper tripeptide; xxviii) 2-20 moles xanthohumol; xxix) 2-20 moles berberine; xxx) 2-20 moles Vitamin F; xxxi) 2-20 moles N-acetyl Glucosamine; xxxii) 2-20 moles Pycnogenol; and xxxiii) 2-20 moles Adenosine; and at least one buffer selected from the group consisting of citric acid, succinic acid, L lactic acid, glycolic acid, malic acid, gallic acid, L-mandelic acid, R-mandelic acid, azelaic acid, d-gluconic acid, sebacic acid, adipic acid, and chlorogenic acid; wherein once reconstituted the composition is characterised as having a pH of from about 3.5 to about 6.

23. A reconstituted cosmetic base composition comprising:

24. A reconstituted cosmetic base composition comprising:

i) calcium ions and magnesium ions, preferably at a molar concentration ratio of 5:1 to 1:1, wherein said calcium ions are at a concentration of from 0.1 to 2.5 mmoles/L; ii) from 2.5 to 6.2 mmoles/L potassium ions; iii) from 96 to 126 mmoles/L chloride ions; iv) from 100 to 150 mmoles/L sodium ions; and at least 4 or more of the following: v) 20-500 pmoles/L polyglutamic acid; vi) 20-500 pmoles/L polylysine; vii) 10-200 pmoles/L zinc pyrrolidine carboxylic acid (L-PCA); viii) 10-100 pmoles/L holo-recombinant human lactoferrin (derived from rice); ix) 1-200 nmoles/L poly-arginine; x) 10-1000 pmoles/L lecithin; xi) 500-1000 pmoles/L niacinamide; xii) 10-100 pmoles/L linoleic acid (LA), and/or alpha LA, and/or oleic acid; xiii) 500-1000 pmoles/L beta-sitosterol; xiv) 500-1000 pmoles/L pantothenic acid; xv) 2-20 mmoles/L D-glucose; xvi) 50-150 pmoles/L diglycerol; xvii) 2-20 pmoles/L talactoferrin; xviii) 150-450 pmoles/L L-glutamate; xix) 2-30piumoles/L L-aspartate; (xx) 200-600 pmoles/L L-glutamine; (xxi) 10-60 nmoles/L thiamine pyrophosphate; xxiii) 2-20 pmoles beta-glucan; xxiv) 2-20 pmoles phlorizin; xxv) 2-20 pmoles asiatic acid; xxvi) 2-20 pmoles copper ion (catalyst)-Cu2+ source; xxvii) 2-20 pmoles copper tripeptide; xxviii) 2-20 pmoles xanthohumol; xxviv) 2-20 pmoles berberine; xxx) 2-20 moles Vitamin F; xxxi) 2-20 tmoles N-acetyl Glucosamine; xxxii) 2-20 tmoles Pycnogenol; and xxxiii)2-20 tmoles Adenosine; and at least one buffer selected from the group consisting of citric acid, succinic acid, L lactic acid, glycolic acid, malic acid, gallic acid, L-mandelic acid, R-mandelic acid, azelaic acid, sebacic acid, d-gluconic acid, adipic acid, and chlorogenic acid; wherein once reconstituted the composition is characterised as having a pH of from about 3.5 to about 6, and that the composition has been reconstituted in a solvent or solvent mixture comprising one or more of ethoxydiglycol, 1,3-butylene glycol, 1,3-propanediol, SD alcohol 40-B, hexyldecanol, dipropylene glycol, 1,2 hexanediol, gluconolactone, Birch sap, and water.

25.A composition according to anyone of claims 1 to 24, wherein the ingredients (other than i) to iv)) (when present) are independently in an amount (%wt/wt of the total composition/formulation) from about 0.001%- 5% wt/wt, such as 0.003, 0.005, 0.01, 0.04, 0.08, 0.10, 0.20, 0.30, 0.50, 0.70, 0.90, 1.1, 1.2, 1.3, 1.5, 1.7, 1.9, 2.0, 2.2, 2.3, 2.5, 2.7, 3.0, 3.3, 3.5, 3.8, 4.0, 4.4, 4.6, 4.8, or about 4.9.

Aug 2021

1/1 2021221835

Figure 1 – Enzyme activity and relationship with pH