WO2018150395A2

WO2018150395A2 - 4-n-butylresorcinol preparations

Info

Publication number: WO2018150395A2
Application number: PCT/IB2018/052742
Authority: WO
Inventors: Natalie Laura ECHEVERRIA
Original assignee: HAKKI, Erkan
Priority date: 2017-02-20
Filing date: 2018-04-20
Publication date: 2018-08-23
Also published as: WO2018150395A3; GB201909518D0; WO2018150395A4; GB201702690D0; GB2562991A

Abstract

A medical or cosmetic formulation such as pastes, gels, lotions, serums, creams, peels and sprays comprising 4-n-butylresorcinol in a concentration greater than substantially 18% preferably between substantially 20% and substantially 60% diluted with a hydrophilic agent, or any diluent known in the art, can be used for treating various skin conditions, e.g. complexion, hyperpigmentation, melasma, pore size, skin density, hydration, superficial scars, post-operative scars, hypertrophic and atrophic scars, post-inflammatory hyperpigmentation, solar lentigines, acne vulgaris and as an anti-aging treatment. The formulae include peels and skincare using various delivery systems, such as liposomal delivery systems and all agents to aide penetration of the epidermis, known in the art. Compositions may include preservatives, such as levulinic acid. Formulation embodiments of the invention can have any one or more of the following features: • Said formulation is between substantially 18% and substantially 60% • Said concentration to produce a skincare treatment • Said concentration to produce a mild peel • Said concentration to produce a medium peel • Said concentration to produce a deep peel • For use in the treatment of any or more of the group comprising: complexion, anti-aging, hyperpigmentation skin disorders, atrophic and hypertrophic superficial and post-operative scars, hydration, skin density, pore size, acne vulgaris • Comprising any one or more of the ingredients mentioned herein for the treatment of melasma • Comprising any one or more of the ingredients mentioned herein for the treatment of hyperpigmentory skin disorders • Another aspect of the invention consists in a method of treating the skin, in which there is used a formulation embodying the invention • A formulation consisting any one of the following: DMSO, levulinic acid, fatty acids such as oleic acid, coconut oil, sources of vitamin C, e.g. rosehip seed, camu camu, infection control such as natural antibiotics e.g. colloidal silver, hydration agents such as glycerin and hyaluronic acid, walnuts, opti zinc, inhibition of collagen synthesis, healing agents such as croton lechleri, tyrosine kinase inhibitors, calcium antagonists such as magnesium, antioxidants such as r lipoic acid, astaxanthin and ubiquinol coqlO, telomeres lengthening agents such as resveratrol and cycloastrogenol, TGF-b inhibitors, protein kinase C (PKC) inhibitors, scar reduction agents such as niacinamide, anti¬ inflammatories such as white willow bark, bamboo, cannabinoids, watermelon skin, agents for collagen stimulation, anti-glycation, immune pathways, red spinach, cherry blossom, tormentil, chitin, rambutan, amino acids, (GL1), (GL3), (TTG1), soursop, oleuropein, cassia, apple skin, osmanthus and all anti-aging agents known in the art. These additional components, may be combined with 4-n-butylresorcinol or may be used separately.

Description

4-N-Butylresorcinol Preparations

Background

Acne Vulgaris is a common skin concern, which primarily effects adolescents and young adults. Various hypotheses exist, but the definitive cause is yet to be established. The pathogenesis of acne is attributed to an increase in sebum production, sebum lipids, androgen activity and bacteria such as Propionibacterium acnes. Subsequent atrophic or hypertrophic scarring is common.

A scar is broadly characterised as the increase of tissue formation or damage to tissue. Scar formation is a natural part of the healing process. Wound healing includes fibroblast proliferation to create collagen, inflammation, granulation and extracellular matrix re-modelling. Treatment of wounds with an emphasis on minimal formation of fibrous tissue, involves infection control, hydration, antiinflammatories, inhibition of collagen synthesis, growth factor (TGF-b) inhibition, calcium antagonists such as magnesium, protein kinase (PKC) inhibition and tyrosine kinase inhibitors, such as genistein.

Anti-aging skincare involves, sun protection, anti-oxidants to combat oxidative stress caused by free radicals, hydration, exfoliation, anti-glycation, stimulation of ceramide levels and maintenance at a cellular level, to promote fibroblast production of collagen, keratinocyte production of keratin and tropoelastin for the maintenance of elastin.

Hyperpigmentation is a common skin disorder, involving the hyperactivity of epidermal melanocytes. Areas of the face develop dark patches of hyperpigmentated skin, causing great distress to patients. The treatment for melasma is challenging, due to its' complex and multifarious diagnoses. Addison's disease, Cushing's disease, pregnancy, oral contraceptives, anti-epilepsy drugs and other medicaments are thought to be possible causes.

Melanogenesis involves melanocytes and surrounding keratinocytes. The melanin pigment is a polymer, which is created within the melanosomes and is synthesised from the amino acid L-tyrosine, which is converted by the enzyme tyrosinase to dopaquinone. Three histological pigmentation patterns have been identified: epidermal, whereby the pigment is deposited in the basal or supra- basal layer; dermal, in the superficial and mid-dermis; and mixed, which is characterised by features of both the epidermal and the dermal patterns. Hypermelanosis may be epidermal (brown), dermal (blue-grey), or mixed (brown-grey).

The use of peels as a skin treatment dates back to ancient times. Peels, especially superficial and medium depth peels, are effective treatment modalities for multiple skin disorders, such as hyperpigmentation, acne, scars and wrinkles. In addition, peels resurface and stimulate cell renewal, to improve the appearance of skin. Peels are the controlled destruction and regeneration of tissue. Peels containing resorcinol, a phenolic derivative, such as Jessner's solution and modify Unna's paste, are widely used and provide good results. The Invention

4-N-Butylresorcinol is both a phenol and resorcinol derivative inhibiting both tyrosinase and tyrosinase related protein T P1. 4-N-Butylresorcinol has a strong protective effect against H202 induced DNA damage and is shown to have anti-glycation effects with no cytotoxicity. This invention relates to the use of 4-n-butylresorcinol using concentrations of substantially 20% up to and including substantially 60% as a skincare preparation for the treatment of melasma, hyperpigmentation, post-inflammatory hyperpigmentation, acne, hypertrophic scars, atrophic scars and as an anti-aging treatment.

Previously, 4-n-butylresorcinol has been tried in skincare preparations, up to approximately 0.1% - 0.5% concentrations. Above this, it has been found to cause skin irritation. These preparations have been used for purportedly lightening the skin, however they do not remove existing hyperpigmentation and the low concentrations of 4-n-butylresorcinol, have minimal effect on tyrosinase and TRP 1 inhibition. This is further to the inability of these preparations to penetrate the epidermis, which is a crucial factor in cases of dermal and mid-dermal hyperpigmentory skin disorders. Clinical data suggests these preparations have little effect on melanogenesis, with reports of minimal epidermal lightening. In cases of melasma, these preparations do not offer cessation of hyperpigmentory activity and are required to be used daily and thus do not provide effective permanent results.

Extensive tests successfully using 4-n-butylresorcinol in much greater concentrations, reveal multifarious benefits. Formulations using greater concentrations established a peeling mechanism to remove hyperpigmentation currently present.

The tests of substantially higher concentrations than heretofore (concentrations of approximately 0.1% to approximately 0.5% used to treat hyperpigmentation, above which percentage it was considered to become a skin irritant) began at 12% and progressed upwardly i.e. to higher concentrations. The marker was established at substantially 20% onwards for treating hyperpigmentation, currently present. This is the optimum results achievable at the lowest possible concentration; with substantially 60% at the highest concentration.

This novel approach to the use of 4-n-butylresorcinol, alters the characteristics of its' prior use into an effective peeling agent to remove existing hyperpigmentation. These treatments may be used as a medical formulation or a cosmetic preparation. The embodiments of these are defined by a non-solid e.g. liquid, lotion, serum, cream, paste, gel or spray.

Peels are the controlled damage of the skin, to reveal a renewed complexion. Peels are used to treat a variety of skin concerns, including hyperpigmentation, acne, scars and as an anti-aging treatment. The skin's pH is ideally regulated, by its' acid mantle to 5.5 pH (though more usually 4.2 to 4.7). Mild peels with a pH level of between 3.0 to 3.5 provide superficial damage, whilst more acidic peels with levels ranging from 1.0 to 2.5 damage more layers of the skin. Peels currently available are classified by their acidic level, these include glycolic, lactic, salicylic and TCA peels. 4-N-Butylresorcinol does not appear to behave as if it is acidic, though it sits at approximately 4.5 pH and does not change with concentration; the peeling mechanism is not determined by the acidic value of the formulation. Tests revealed no change in pH value at 27% concentration and at 60%.

Mild peels using 4-n-butylresorcinol were devised as a treatment for existing hyperpigmentation. The advantage of using mild peels, as opposed to medium or deep peels, is that they can be layered to increase strength, if required, and the peeling action can be controlled to suit the lifestyle of the patient, thus reducing the need for 'downtime'. A dermal plate has also been developed to assist with penetration of the mild peels, to enhance delivery. Preparations using 4-n-butylresorcinol were diluted with a hydrophilic agent, preferably glycerin and/or glycol, or other suitable diluents known in the art. Further peels were devised for cases of dermal and mid-dermal hyperpigmentation at varying concentrations.

It is apparent, that the use of peels as a treatment modality to remove existing hyperpigmentation, are effective. As previously mentioned, phenolic peels, such as Jessner's solutions provide good results to treat hyperpigmentation. However, clinical data suggests there are toxicity concerns regarding the use of resorcinol. Clinical studies reveal no cytotoxicity issues with the use of 4-n-butylresorcinol.

Another benefit of the novel use of 4-n-butylresorcinol as a peeling agent, is its' inhibitory effects on tyrosinase and tyrosinase related protein T P1, to not only remove hyperpigmentated skin, but as a treatment for melasma. Treatment of hyperpigmentory disorders requires the removal of hyperpigmentated skin, which is currently present and regulation of dermal and epidermal melanin synthesis via tyrosinase inhibition.

Hydroquinone is a tyrosinase inhibitor and is widely used as a treatment for hyperpigmentory disorders. Hydroquinone is a phenolic compound and de-pigmenting agent that mainly exerts its effect on melanocytes with active tyrosinase. As hydroquinone dependent melanogenic inhibition requires the presence of active tyrosinase, it is not useful in altering the colour of melanin that is previously present in the dermis and epidermis.

The structural similarity between hydroquinone and melanogenic precursors enables hydroquinone's interaction with tyrosinase. This interaction mediates hydroquinone's inhibition of tyrosinase by binding histidines or copper at the active site of the enzyme. Additionally, hydroquinone induced generation of reactive oxygen species and quinones leads to the oxidative damage of membrane lipids and proteins such as tyrosinase. Hydroquinone is also thought to inhibit pigmentation by depleting glutathione, modifying melanosome formation or reducing DNA and RNA synthesis with concomitant melanosome degradation and melanocyte destruction.

Due to the risks of side effects such as exogenous ochronosis and permanent depigmentation following long term use, hydroquinone has been banned by the European Committee (24^th Dir 2000/6/EC) and formulations have been withdrawn from cosmetics and are available via prescription, only.

The aforementioned preparations have an added disadvantage. These formulations are devised without capabilities to allow penetration of the epidermis. This is an important factor for treatment of dermal and mid-dermal hypermelanosis.

Tools such as micro-needling kits serve to assist with the penetration of substances. Another option is the inclusion of agents known in the art, to drive the molecules. Agents include, emu oil, DMSO, fatty acids such as oleic acid, caffeic acid and urea, to name but a few.

4-N-Butylresorcinol is a tyrosinase and TRP1 inhibitor and both a phenolic and resorcinol derivative, but with no cytotoxicity and has multiple effects on melanin synthesis. It inhibits tyrosinase and related melanogenic enzymes, regulating melanocyte homeostasis and the alteration of constitutive and facultative pigmentation and the down regulation of melanosome transfer to the keratinocytes.

I herein use the term Nabuti, to mean 'a treatment with natural botanicals together with 4-n- butylresorcinol'. (Outside this specification, the term Nabuti^® is a registered trade mark). All formulations are created using organic food-grade substances. The botanical waters are extracted from e.g. kiwi and the preparations are preserved using food-grade preservatives, such as levulinic acid.

In accordance with the guidelines, 4-n-butylresorcinol has substantial and useful penetrative properties. These are further enhanced with the inclusion of various delivery systems known in the art e.g. liposomes. The embodiments disclosed herein are of medical and cosmetic grade formulations. They may be pharmaceutical preparations and / or cosmeceutical preparations, which latter term may include medical and cosmetic grade preparations that can be used on the skin e.g. for treatment and prevention of diseases of the skin.

The treatment of melasma is complex due to its' multifarious diagnoses. A study was conducted, in order to establish possible causes and to measure the efficacy of the Nabuti^® melasma treatment.

Summary of In-Vivo Melasma Study

The study was undertaken in compliance with Good Clinical Practice (GCP) and in adherence to Good Manufacturing Practice (GM P). Eighty-Five women, between the ages of 32-45, exhibited symptoms, including dermal and epidermal melasma. The degree of severity of melasma was evaluated by the use of the MASI scoring system. All participants were previously resistant to other modes of treatment with recurrence. Any individual meeting the following criteria was excluded from the study:

Pregnant, breastfeeding, skin infections such as herpes simplex virus, keloid formation, melanoma, collagen vascular disease and bleeding disorders. In addition, all participants were requested to stop use of any retinoids or other hypopigmentating treatments six months prior to enrolment onto the study.

It is not surprising that each participant exhibited a unique set of symptoms accompanying the diagnosis of melasma. Symptoms included: thick coating on tongue, lethargy, bloated abdomen, thick vaginal discharge with unpleasant odour, low mood, irritability, joint pains and muscle aches. All participants underwent a series of diagnostic tests. These included Cortisol levels, thyroid function, heavy metals such as copper, medicaments, nutritional and hormonal imbalances and food allergies. These tests revealed a form of impediment to homeostasis with subsequent symptoms, accompanied by melasma. However, the majority of the participants were found to be gluten intolerant and / or yeast intolerant, with some cases further complicated by leaky gut syndrome. It is also noted that further complications due to medicaments such as anti-depressants and pain killers, were also present.

The next aim of the study was to determine overproduction of melanin as a result of an impediment to homeostasis and assess the efficacy of the Nabuti^® melasma treatment.

For the purposes of the patent literature one group of participants will be the subject matter. The group to be discussed is food intolerance i.e. gluten and/or yeast with / without complications.

Forty women were given a healthy gluten free and/or yeast free diet plan for six months. The remaining participants began the Nabuti^® melasma treatment. Participants were advised not to use any other skincare products, during the treatment. Each participant dependent on the diagnosis was given a treatment plan comprising of peels of varying strengths, along with a post-peel care plan. This was accompanied by a healing ointment and tinted sun protection cream. The forty women following a gluten and/or yeast free diet for six months, remained on the diet and began the melasma treatment. The entire process was replicated. All participants tolerated the melasma treatment well, with no reported side effects. Both groups completed the melasma treatment and tests revealed a MASI score of 0, for dermal, mid-dermal and epidermal hyperpigmentation.

Observations were carried out at the three, six, nine, twelve and eighteen month stages, post melasma treatment. The group abstaining from gluten and/or yeast had a MASI score of 0, at the eighteen month stage. The gluten / yeast group had a MASI score of 0 at three and six months. Obvious increase of production of melanin was observed at approximately the seven month stage, without the presence of the regulatory effects of the Nabuti^® treatment. However alternative treatments such as hydroquinone and deep peels provide relief from visible hyperpigmentation, four weeks and three weeks respectively.

Further observations, demonstrated hypermelanosis is more sustained. Regulation of melanin production is observed for approximately six months. A MASI score of 1 was observed at approximately the six to seven month stage. Pigmentation is no longer localised. Dark patches are no longer visible, even at the eighteen month stage, but instead the pigmentation is dispersed, to create a uniform appearance. Sun exposure has no effect on the rate of melanin production. It is also noted that individuals with a tendency to burn easily, observed greater resilience to UV radiation.

In view of these observations, further compositions were devised to maintain the regulatory effects of the Nabuti^® treatment. The maintenance system provides good results. Participants of the study showed no abnormal melanin production with tests revealing a MASI score of 0, at thirty months, post the melasma treatment.

In conclusion, melanin is created as a protective mechanism, commonly observed with exposure to ultraviolet radiation. It is therefore evident, melasma, is the over production of melanin, due to the body's need to protect itself from a toxic substance or other impediment to homeostasis. It is recommended that tests be carried out to ascertain whether hormonal imbalances, high levels of heavy metals, nutritional imbalances, food allergies, leaky gut syndrome, medicaments and other 'toxic' substances are present, as a cause in an individual diagnosed with melasma.

Independent studies confirm hydroquinone is an effective treatment modality to combat melasma, but it is also proven to cause serious side effects. The tests, as outlined, confirm 4-n-butylresorcinol provides superior results, compared with hydroquinone and does not cause serious side effects. The novel use of 4-n-butylresorcinol in higher concentrations, provides greater results and is advantageous for the treatment of dermal and mid-dermal melasma.

Melasma Treatment

The first stage of the treatment for melasma must include an individualistic approach to establish the cause. It is imperative that tests be carried out to detect food allergies, toxic substances such as high levels of heavy metals, nutritional imbalances and hormonal imbalances.

Upon identifying the possible cause, the next stage involves detoxification and/or tailored diet. The time required to achieve homeostasis varies.

The homeostasis diets are available to participants, tailored to the needs of the individual and are prescribed following a full assessment by a professional practitioner, incorporating criteria, such as age and gender. In addition, food plans targeting busy households are provided, to ensure realistic goals. Homeostasis is the balance of all systems, including the integumentary system. This is a vital component if a patient desires the best outcomes or indeed any non-surgical treatment and it is equally relevant to surgical treatments and the wound healing process. For example, if a food allergy is known as the cause of overproduction of melanin, it is advised that the patient abstain and eliminate that which the body sees as a toxic substance. If the overproduction of melanin is not addressed and the patient undergoes treatment for scar removal, independent studies confirm that treatments involving wound healing are greatly compromised and will therefore not provide the best results attainable.

The process of elimination, is accelerated by the inclusion of the Perque detox program, followed by an uptake of supplements, such as, spirulina, probiotics, sulphur, mineral pitch, aloe vera, magnesium, and charcoal. Once the symptoms are alleviated stage two of the treatment may commence, with the introduction of the food plan.

A generic diet based on age and gender with the aid of supplementation has been developed targeting busy households. The diet is quick and easy and covers all aspects of the maintenance of the body 'homeostasis maintenance'. To follow is a list of some of the supplements, which form part of this diet:

Saffron, I theanine, white willow bark, golden root, sulphur, spirulina, kelp, mineral pitch, r lipoic acid, I citrulline, white spruce, zinc (opti), biotin, KSM 66 ashwagandha, ubiquinol coQ.10, astaxanthin, sumac bran, niacinamide, BCM 95 curcumin, lion's mane, reishi, cordyceps, black seed oil, camu, xanthohumol (luciden form), Eummia Ulmoides, eleuthero, frankinsense, probiotics and I glutamine, to name but a few. Directions for use, accompany the menu for breakfast, lunch and dinner, with nutritious smoothies and desserts, needing minimal preparation time.

The third and final stage of the treatment is a course of topical peels, this includes preparation and post treatment care.

Preparation

1. A blend of organic food-grade oils to remove make up.

2. A cleansing food-grade water made of crystal water, megahydrate powder, organic papaya and organic Moringa Oleifera.

3. Skin plate of pure DMSO bathed in organic cape stem cells without aloin.

Melasma Peel

To follow is a list of ingredients used to influence distinct steps of melanin synthesis:

1. 4-N-Butylresorcinol - Tyrosinase inhibitor, T P1 inhibitor

2. Resveratrol of Japanese Knotweed - TRP2 inhibitor, TGF beta inhibitor

3. Curcumin of Turmeric - PKC inhibitor, Alpha MSH inhibitor

4. Fucoidan of Kelp - Autography, TGF beta 1 inhibitor

5. Sulphur - Glutathione optimisation

6. White Willow Bark - Anti-inflammatory

7. Ellagic Acid of Pomegranate - Copper chelation

8. Niacinamide - Melanosome transfer inhibitor

9. Ferulic acid of Angelica Sinensis - Tyrosine oxidation inhibitor Post-Peel Care

1. Organic aloe cape stem cells ointment

2. Organic healing balm

3. Organic tinted sun protection lotion

The results of the melasma study illustrate use of 4-n-butylresorcinol as a peeling agent in high concentrations as an effective treatment to combat melasma, with no concerns regarding toxicity. This novel approach to the use of 4-n-butylresorcinol offers a distinct advantage by combining the properties of 4-n-butylresorcinol as a potent tyrosinase inhibitor and T P1 Inhibitor with its' ability to perform as a peeling agent to both peel and treat multiple layers of the skin simultaneously, which is especially beneficial for the treatment of dermal melasma. By increasing the concentration, 4-n- butylresorcinol is not only more effective, but it is successful as a maintenance and treatment by adding to the formula various delivery methods to enhance penetration.

Data gathered during the eighteen month period post melasma study revealed, further positive outcomes. Independent examinations confirmed marked improvement in unrelated skin disorders, notably acne vulgaris and atrophic scars. Overall improvement in the appearance of skin with increase of collagen and significant improvement in global firmness and jaw-line contour was also observed. Revisions to the original formula were developed and distinct compositions were devised respectively.

Preliminary observations were conducted based upon these new compositions. The study models albeit small exhibited substantive results. The findings from these initial examinations revealed a vast reduction in the prevalence of nodulocystic acne. The appearance of scars such as rolling, ice-pick, punched and boxcar scars of depths graded as macular, mild, moderate and severe were dramatically improved. Even more remarkable were the results obtained from the treatment of hypertrophic and atrophic post-operative scars, whereby scars were barely visible after only four applications. The anti- aging treatment demonstrated a significant reduction in wrinkles, pores were minimised, elasticity measured by cutometry was greatly improved, ceramide levels were increased with decreased transepidermal loss and increase of type I III V collagen.

These preliminary findings along with the compositions for acne vulgaris, anti-aging, scars and wound healing are to be assigned to an independent body to perform independent thorough quantitative clinical trials. A comprehensive insight will provide a full appreciation of the compositions and their integral roles, respectively. At this stage, disclosure by what method efficacy is achieved would be entirely speculative and misleading. Hence, upon completion of the aforementioned studies, it is hoped, a full understanding of the processes involved by which these results are obtained shall be divulged and for these findings to be published, as per the protocol governing clinical trials.

The Nabuti^® melasma treatment, in the later part of this description lists the ingredients used to influence distinct steps of melanogenesis, by using a synergistic blend of botanicals, along with 4-n- butylresorcinol. These preparations can be formulated as a peel or penetrative cream, serum, spray, paste, lotion or gel. A number of ingredients mentioned herein in relation to melasma and hyperpigmentation can form part of the compositions used in the acne, scars, wound healing and anti- aging treatments. These ingredients include:

DMSO, levulinic acid, fatty acids such as oleic acid, coconut oil, sources of vitamin C, e.g. rosehip seed, camu, infection control such as natural antibiotics e.g. colloidal silver, hydration agents such as glycerin and hyaluronic acid, walnuts, opti zinc, inhibition of collagen synthesis, healing agents such as croton lechleri, calcium antagonists such as magnesium, antioxidants such as r lipoic acid, astaxanthin and ubiquinol coqlO, telomeres lengthening agents such as resveratrol and cycloastrogenol, TGF-b inhibitors, protein kinase C (PKC) inhibitors, scar reduction agents such as niacinamide, antiinflammatories such as white willow bark, bamboo, cannabinoids, watermelon skin, agents for collagen stimulation, anti-glycation, immune pathways, red spinach, cherry blossom, tormentil, chitin, rambutan, amino acids, (GL1), (GL3), (TTG1), soursop, oleuropein, cassia, apple skin, osmanthus and all anti-aging agents known in the art. These additional components, may be combined with 4-n- butylresorcinol or may be used separately.

The advantages of 4-n-butylresorcinol extending beyond the treatment of hyperpigmentory skin disorders have only just been discovered. Further studies into 4-n-butylresorcinol, will reveal its' multifarious benefits as a treatment for acne vulgaris, atrophic and hypertrophic scars and as an anti- aging treatment.

Claims

1. A skin formulation of a peel, spray, paste, gel, lotion, serum, cream.

2. A medical or cosmetic skin formulation comprising 4-n-butylresorcinol in a concentration greater than substantially 18%.

3. A formulation as claimed in claim 2, in which said concentration is between substantially 20% and substantially 60%.

4. A formulation as claimed in any preceding claim, for use in a treatment to produce a mild peel.

5. A formulation as claimed in any preceding claim, for use in a treatment to produce a medium peel.

6. A formulation as claimed in any preceding claim, for use in a treatment to produce a deep peel.

7. A formulation as claimed in any preceding claim, for use in the treatment of hyperpigmentory skin disorders.

8. A formulation as claimed in any preceding claim, for use in the treatment of acne vulgaris.

9. A formulation as claimed in any preceding claim, for use in an anti-aging treatment.

10. A formulation as claimed in any preceding claim, for use in the treatment of any one or more of the group comprising complexion: pore size, skin density, hydration.

11. A formulation as claimed in any preceding claim, for use in the treatment of facial hypertrophic and atrophic scars.

12. A formulation as claimed in any preceding claim, for use in the treatment of hypertrophic and atrophic scars of the body.

13. A formulation as claimed in any preceding claim, for use in the treatment of post-operative hypertrophic and atrophic scars.

14. A formulation as claimed in any preceding claim, diluted with a hydrophilic agent, or any diluent known in the art.

15. A formulation as claimed in any preceding claim, with a preservative such as levulinic acid, or any other preservative known in the art.

16. A formulation as claimed in any preceding claim, without a preservative.

17. A formulation as claimed in any preceding claim, using any delivery system, such as liposomal delivery systems and all agents to aide penetration of the epidermis, known in the art.

18. A formulation as claimed in any preceding claim, comprising any one or more of the ingredients mentioned herein for the treatment of hyperpigmentation.

19. A formulation as claimed in any preceding claim, comprising any one or more of the ingredients mentioned herein for the treatment of melasma.

20. A formulation as claimed in any preceding claim, comprising any one or more of the following ingredients: DMSO, levulinic acid, fatty acids such as oleic acid, coconut oil, sources of vitamin C, e.g. rosehip seed, camu camu, infection control such as natural antibiotics e.g. colloidal silver, hydration agents such as glycerin and hyaluronic acid, walnuts, opti zinc, inhibition of collagen synthesis, healing agents such as croton lechleri, tyrosine kinase inhibitors, calcium antagonists such as magnesium, antioxidants such as r lipoic acid, astaxanthin and ubiquinol coqlO, telomeres lengthening agents such as resveratrol and cycloastrogenol, TGF-b inhibitors, protein kinase C (PKC) inhibitors, scar reduction agents such as niacinamide, antiinflammatories such as white willow bark, bamboo, cannabinoids, watermelon skin, agents for collagen stimulation, anti-glycation, immune pathways, red spinach, cherry blossom, tormentil, chitin, rambutan, amino acids, (GL1), (GL3), (TTG1), soursop, oleuropein, cassia, apple skin, osmanthus and all anti-aging agents known in the art.