WO2008050157A2

WO2008050157A2 - Ozonated oil formulations

Info

Publication number: WO2008050157A2
Application number: PCT/GB2007/050654
Authority: WO
Inventors: Steven Karim
Original assignee: Steven Karim
Priority date: 2006-10-24
Filing date: 2007-10-24
Publication date: 2008-05-02
Also published as: WO2008050157A3

Abstract

A pharmaceutically or cosmetically acceptable oil that has been ozonated with an amount of ozone less than the amount required to saturate the oil, pharmaceutically o r cosmetically acceptable formulations comprising such an oil for topical application to the skin, and various pharmaceutical and cosmetic uses of such an oil.

Description

Ozonated oil formulations

Description

The present invention relates to ozonated oils. In particular, it relates to oils ozonated to different levels, to pharmaceutically or cosmetically acceptable formulations comprising these oils for topical application to the skin, and to various pharmaceutical and cosmetic uses of these oils.

Research in the dermatological field is ever-expanding, not least because the skin is the largest organ of the body and plays a wide range of important roles. Common skin diseases or conditions include eczema, acne, psoriasis, skin cancer, viral warts and uticaria. Whereas some skin disorders are isolated, others are symptoms of internal disease, such as rheumatic disease. Topically administered treatments are widespread, ranging from simple zinc- and titanium-based emollients to soothe and hydrate the skin, to creams containing active agents like antibiotics to treat infections and steroids to treat inflammatory conditions such as eczema and psoriasis. However, orally administered agents have also been used, such as the retinoid isotrenitoin for severe forms of acne, and ultraviolet light has been employed to treat diseases such as mycosis fungoides.

There are a number of problems with the known treatments for skin disorders. For instance, many antibiotic creams are too powerful for long-term use, and serious side effects have been associated with steroid therapy, including skin atrophy and steroid allergy. Alternatives to these creams have thus been keenly sought in the art.

There has been some investigation into ozonated pharmaceutical formulations, most commonly olive oil based formulations, as ozone is known to have useful properties such as microbicidal activity. For instance, FR 2,784,388 discloses the pharmaceutical and cosmetic use of oils such as olive oil that have been ozonated to saturation. US 4,451 ,480 discloses ozonized oils such as olive oil, jojoba oil and sesame oil for topical application to the skin for the treatment of acne, which have an active oxygen content of about 0.1 to about 15 % by weight of the ozonide component.

There have been problems associated with ozonated olive oil formulations, however. WO 2006/021924 notes that ozonated olive oil is unstable due to its chlorophyll content and the relatively high concentration of short chain fatty acids relative to long chain fatty acids. It discloses ozonated avocado oil for therapeutic and cosmetic use and a method of producing such an oil. It notes that avocado oil has a higher concentration of long chain fatty acids relative to short chain fatty acids, and in the invention the chlorophyll naturally present is removed before ozonation. Nevertheless, this document does not consider suitable ozonation levels of the oil nor correlate these with particular pharmaceutical uses.

For a number of reasons, ozonated formulations have been slow to gain widespread acceptance for pharmaceutical use. If the majority of the known ozonated oils are applied to the skin on a regular basis, their high ozone concentration causes overstimulation of cells, producing undesired effects such as irritation, rashes and even rapid flaking of the skin. In some cases, the strong smell of ozone is unpleasant and causes the eyes to water. Furthermore, others of the known oils have non-specific physiological effects that are hard to control.

In seeking to overcome one or more of the above-mentioned problems, a range of ozonated oils have been developed that may be tailored to particular therapeutic uses, and that have also been found to have advantageous properties in the cosmetic field.

Accordingly, in a first aspect of the invention there is provided a pharmaceutically or cosmetically acceptable oil that has been ozonated with an amount of ozone less than the amount required to saturate the oil.

In a second aspect of the invention there is provided avocado oil ozonated with 1.0 - 6.0 g of ozone per 100 g of oil. In a third aspect of the invention there is provided ozonated avocado oil containing 1.0 — 6.0 % ozonated compounds.

In a fourth aspect of the invention there is provided a pharmaceutically or cosmetically acceptable formulation comprising an oil according to the invention in any of its first to third aspects, for topical application to the skin.

In a fifth aspect of the invention there is provided a lip balm, moisturiser, facial, cleanser or anti-aging product, or massage oil comprising a formulation according to the invention in its fourth aspect.

In a sixth aspect of the invention there is provided the use of a formulation according to the invention in its fourth aspect as a lip balm, moisturiser, facial, cleanser or anti-aging product, or as a massage oil.

In a seventh aspect of the invention there is provided an oil according to the invention in any of its first to third aspects for use in therapy.

In an eighth aspect of the invention there is provided the use of an oil according to the invention in any of its first to third aspects for the manufacture of a medicament for use in the treatment or prophylaxis of a dermatological condition, disease or disorder.

Preferred embodiments of the invention are as set out below or as defined in the sub-claims.

Figure 1 illustrates various regions of the skin and underlying adipose tissue, and penetration of ozone and/or ozonides through these regions.

The oils of the present invention have one or more beneficial properties and may be used as pharmaceuticals, cosmetics or so-called "cosmeceuticals". For instance, they may be antibacterial, antiviral and/or antifungicidal. They exert a rapid and - A -

efficient sterilizing effect, produce an improvement and acceleration of skin and tissue healing and are efficient immunoactivators.

They may stimulate blood circulation, improving the rheological properties of red blood cells, activating red blood cell metabolism, shifting the HbO₂/Hb balance to the right and improving the release of oxygen. They may cause an increase in adenosine triphosphate (ATP), an increase in 2,3 diphosphoglycerate (2,3 DGP) and a drop in glutathione (GSH).

In immunocompetent cells, the inventive oils may activate nuclear factor NFkB, and cause an induction and release of cytokines such as IL-I, IL-2, IFN-γ, TNF-OC and TGF-β.

The oils used have a maximum amount of ozone that can be incorporated, either by reaction or otherwise. The oils of the invention are ozonated with an amount of ozone less than this maximum amount required to "saturate" the oil. They have been found to have fewer side effects than the known saturated oils, whilst still maintaining therapeutic efficacy. In particular, skin is made up of several layers, including the epidermis, papillary dermis and reticular dermis, as shown in Figure 1, and the oils of the invention have various levels of action within the skin cells, blood cells, sebaceous glands, nerve tissue, muscle tissue and skin pores. By varying the concentration of ozone or ozonated species in the oil, the depth of penetration through the skin and the effects at a cellular level can be controlled and specifically tailored according to its desired use.

The well known cold corona discharge method may be used to produce so-called medical grade ozone (typically a 0.05 - 5 % mixture of O₃ and O₂) from medical grade oxygen. The oil is placed into a pressurised vat and the medical grade ozone can then be bubbled through until the desired ozonation level has been reached. The method disclosed in WO 2006/021924 may be used. Where the exact composition of the oil is batch dependent, one can take a known quantity of oil, measure the time required to ozonate to saturation and then calculate the time required to ozonate to the desired concentration. In this manner, ozone is "stabilized" and the ozonated oil has a relatively long shelf life, e.g. twelve months if stored at low temperatures.

In a preferred embodiment of the invention, the oil contains unsaturated compounds, i.e. compounds bearing carbon-carbon double bonds. Preferably, these compounds are unsaturated fatty acids.

The exact composition and mechanism of action is not fully understood. However, it is believed that when ozone gas is introduced, at least part of it may react to form compounds such as ozonides, aldehydes or lipoperoxides. The Criegee mechanism may be involved in these reactions. When applied to the skin, the ozonation products may pass through to the intercellular space of red blood cells and immunocompetent cells to influence cellular metabolism.

At least a part of the ozone introduced into the oil may remain in associated but unreacted form, for example in sequestered form or as a clathrate. Alternatively or in addition to the mechanisms outlined above, after application to the skin the ozone may be released and may break down to form oxygen free radicals, which are highly reactive and damage or destroy foreign organisms. Concurrently, it may stimulate the production of enzymes in the cell wall of the body's own cells such as glutathione peroxidase, catalase and superoxide dismutase, thus enhancing the cell wall resistance to attack by ozone.

The most preferred oil for use in the present invention is avocado oil. Analysis shows that the oil contains essential vitamins, minerals and fatty acids that are good for skin nutrition. In addition, it contains a rare DNA component that stimulates the skin to regenerate its own natural collagen (which provides skin elasticity). Unlike other plant oils, it has a high natural concentration of antioxidants such as vitamin E, which are absorbed through the dermal layers and are known to combat aging of living cells. It is suspected that ozonation gives rise to a synergistic effect at a cellular level with the vitamin E naturally present, since vitamin E stabilizes the structure of the biomembrane by scavenging free radicals, protecting against the generation of damaging lipoperoxides in the biomembrane.

Where the oil to be ozonated contains chlorophyll, this can optionally be removed before ozonation.

The oil of the invention may be useful in the treatment or prevention of a variety of different dermatological conditions, diseases or disorders, including acne, actinic keratosis, angioma, aquagenic pruritus, athlete's foot, atopic dermatitis, baldness, basal cell carcinoma, bed sores, Behcet's disease, blepharitis, Bowen's disease, bullous pemphigoid, canker sores, carbuncles, cellulitis, chloracne, dyshidrosis, cold sores, creeping eruption, dermatitis, dermatitis herpetiformis, dermatofibroma, diaper rash, eczema, epidermolysis bullosa, erysipelas, erythroderma, genital warts, hidradenitis suppurativa, hives, hyperhidrosis, ichthyosis, impetigo, Kaposi's sarcoma, keloid, keratoacanthoma, keratosis pilaris, lichen planus, lichen simplex chronicus, lipoma, lymphadenitis, malignant melanoma, melasma, miliaria, molluscum contagiosum, nummular dermatitis, Paget's disease of the nipple, pediculosis, pemphigus, perioral dermatitis, photoallergy, pityriasis rosea, pityriasis rubra pilaris, psoriasis, Raynaud's disease, ring worm, rosacea, scabies, scleroderma, sebaceous cyst, seborrheic keratosis, seborrhoeic dermatitis, shingles, skin cancer, skin tags, spider veins, squamous cell carcinoma, stasis dermatitis, tick bites, tinea barbae, tinea capitis, tinea corporis, tinea cruris, tinea pedis, tinea unguium, tinea versicolor, tinea, tungiasis, vitiligo, or warts.

The formulation of the invention having an ozonation level of 1.0 - 2.0 % is particularly suitable for use as a lip balm. It helps to prevent the lips from cracking and drying out and is advantageously applied sparingly once to three times per day. The low ozone concentration provides cellular granulation to the skin cells on the lips, allowing them to regenerate at an optimum rate thus accelerating healing time.

The formulation of the invention having an ozonation level of 2.0 - 3.0 % is particularly suitable for use as a moisturiser. It is thought to primarily act on the epidermis, conditioning and brightening the complexion and regulating oil glands. Angiogenesis promotes microcapillaries to increase blood circulation into the skin layers. The antioxidants such as vitamin E present in avocado oil also protect against environmental pollutants and free radicals generated by UV from the sun. This formulation provides cellular granulation to the skin cells and neutralizes excess acids, balancing skin pH to a more alkaline level. It is preferably applied daily and to the face.

The formulation of the invention having an ozonation level of 3.0 — 4.0 % is particularly suitable for use for facials, as a cleanser or as an anti-aging product. It is thought to primarily act on the epidermis and dermal layers, and provides an increased reaction process of repair and replication at a cellular level, cleaning the lymphatic channels around the face and providing antibacterial and viral protection against skin infection within the pores of the skin. This builds a much stronger layer of healthier skin cells, well before the cells mature, thereby lifting the tone and texture of the skin, providing soft smooth complexion with increased elasticity and delaying the aging process of the cells. Further, it cleanses sweat glands, neutralizes toxins and balances skin pH, reducing spots and pimples. It is preferably used once to three times per week, and stored in a dark and cool place out of direct sunlight.

The formulation of the invention having an ozonation level of 4.0 - 5.0 % is particularly suitable for use as a massage oil, especially for sports massage. It is thought to act upon the epidermis, dermal layers, nerve and muscle tissue, conditioning the skin but also reducing aches and pains in muscles, reducing lactic acid build up and increasing ATP in the muscle cells. It aids healing of damaged muscles, ligaments and tendons, for instance in sports injuries, and can also be used to increase stamina in the muscles and reduce recovery periods after strenuous exercise or sports. It can be applied all over the body, or in specific areas such as to lymphatic zones to cleanse the lymphatic channels and lymph nodes and aid lymphatic circulation, and also to boost the immune system by increasing immunoproteins. It may be used every day, and is preferably stored in a cool dark place out of direct sunlight. The formulation of the invention having an ozonation level of 5.0 — 6.0 % is particularly suitable for use as a cosmeceutical or pharmaceutical. It penetrates deeply through the skin and can be used to treat a whole range of dermatological conditions including a wide spectrum of acne, cold sores and spots. It has a strongly sterilizing and cleansing effect, conditioning the skin to deal with most types of acne and spots. It can also be used to treat other skin ailments such as psoriasis, eczema, skin cancer and disorders associated with Type I diabetes. It may be used daily and left overnight, and may be applied sparingly over the affected area using an implement such as a cotton bud.

The oils of the invention range in colour and consistency depending on ozone concentration and temperature; they may take on a solid form with a creamy consistency or may be a viscous oil.

The oils may be used per se, without any excipients. If desired, however, other cosmetically or pharmaceutically acceptable ingredients may be included in the formulations, such as aromatic essential oils to mask the odour of ozone.

Example 1 — Measurement of the effect of the ozonated oils of the invention on the oxygen supply in the skin

Measurements of skin oxygen saturation (SO₂) are carried out using a Whitland Research RM200 tissue SO₂ monitor using two probes with different catchment depths: one which measures predominantly in the capillaries of the subpapillary plexus, the other which encompasses the venous plexus and some vessels of the deep dermal plexus.

Healthy human volunteers without a Latex allergy are acclimatised at ambient 23 ⁰C for 15 minutes, and 3 sites of area approximately 1 cm² are chosen on the right cheeks of the subjects and a fourth site on the left. The sites are chosen to avoid any visible veins, blemishes or pigmentations, and are marked discretely so that the same sites can be located for the subsequent measurements. Initial, baseline measurements with both probes are carried out at all four sites. On each occasion, approximately 10 measurements are made over the area of each site.

An ozonated oil of the invention is then applied by gentle massage to the first test site on the right cheek. The same oil, but not containing ozone, is similarly applied to the second site on the right cheek. The third site on the right cheek and the fourth site on the left cheek is similarly massaged, but without the application of any oil (both are considered as control sites, one on each side). Subsequent measurements are carried out at all 4 sites using the 2 probes at 30 minutes, 1 hour, 6 hours and 24 hours following application of the oils.

Results are analysed using the mean SO₂ values measured at each site, treating the results from the 2 probes separately, and appropriate statistical techniques are applied.

Example 2 - Treatment of dyshidrotic eczema

In the course of treating a female with dyshidrotic eczema, avocado oil ozonated to a concentration of 2.61 % was applied to her hands twice daily, in the morning and at night. After some initial inflammation on the right hand, both hands healed completely after a relatively short period of time. Use of this serum thus allowed the condition to be stabilized and healing occurred at a greater healing rate than with previously used products.

Example 3 — Treatment of acne Candida is an opportunistic yeast that normally resides harmlessly in the digestive system. In the abnormal state, however, Candida proliferates and converts into an invasive form to spread from the intestinal tract into the blood stream. This is known as a systemic Candida infection. One of the many symptoms from Candida is severe acne that ranges from white heads, papule, pustules and nodules.

A female who had been suffering with Candidasis for two years had all four symptoms of acne mentioned above. The healing rate of her skin was slow due to the life cycle of the nodules and papule, and her skin had very little time to recover due to new outbreaks that occurred regularly, especially when she menstruated.

She was given avocado oil ozonated to a concentration of 3.62 % to be massaged well into the affected areas for 10 minutes every night, and left to be absorbed overnight. In just under one month the outbreaks had begun to slow down, the redness had decreased by 70% and the purple colourisation had completely disappeared. The nodules had shrunk by 50%, the pain, itchiness and irritation had disappeared and only papule acne was coming out through the skin, decreased by 70%. With continued treatment the skin started to become soft and showed signs of smoothness. Subsequent new outbreaks, correlating with the timing of the patient's menstrual cycle, were less severe than previously experienced and began to heal at an accelerated rate, within a matter of days.

Example 4 - Treatment of acne

A female presented a severe spread of acne (white heads and papules) around both shoulders and back. Previously used cleansing products and acne creams had had an effect but had not stopped the continuation of outbreaks of the spots. The papule spots cycle lasted a month before they disappeared.

Her treatment plan involved cleansing the affected areas with warm water and exfoliant, followed by application of sparing amounts of the serum directly onto the skin and massage with pressure for 20 — 25 minutes until a warming heat was produced, twice per week.

Two days after the first treatment, the soreness and pain was no longer present. Just before the third treatment the skin was soft and smooth in all the affected areas; all papules had been eliminated with no reoccurrence since the second treatment and all white heads have been eliminated apart from two fresh ones on the shoulders. After the third treatment, there was no reoccurrence of white heads or papules on the affected areas, and the skin remained bright, vibrant, smooth and soft. The serum provided a superior healing rate and effective treatment for acne. It continued to work after each treatment due the ozonides that were stored at a cellular level to continue the healing process in between each of the treatment sessions.

Claims

1. A pharmaceutically or cosmetically acceptable oil that has been ozonated with an amount of ozone less than the amount required to saturate the oil.

2. An oil according to claim 1, that has been ozonated with 10 - 70 %, preferably 30 — 50 %, of the amount of ozone required to saturate the oil.

3. An oil according to claim 1 or 2, containing unsaturated compounds, preferably unsaturated fatty acids.

4. An oil according to claim 3, containing a higher concentration of long chain fatty acids relative to short chain fatty acids.

5. An oil according to any of the preceding claims, wherein at least part of the ozone reacts with the oil, preferably to form lipoperoxides, ozonides or aldehydes.

6. An oil according to any of the preceding claims, comprising ozone in unreacted form, in sequestered form or as a clathrate.

7. An oil according to any of the preceding claims, containing at least one antioxidant, preferably vitamin E.

8. An oil according to any of the preceding claims, comprising ozonated compounds capable of passage through to the intercellular space of red blood cells and immunocompetent cells upon application of said oil to the skin.

9. An oil according to any of the preceding claims, which releases or causes the generation of active oxygen species, preferably free radicals or hydroxyl radicals, upon application to the skin.

10. An oil according to any of the preceding claims, which traps free radicals or suppresses their generation in vivo.

11. An ozonated avocado oil according to any of the preceding claims.

12. Avocado oil ozonated with 1.0 — 6.0 g of ozone per 100 g of oil.

13. Ozonated avocado oil containing 1.0 - 6.0 % ozonated compounds.

14. A pharmaceutically or cosmetically acceptable formulation comprising an oil according to any of the preceding claims, for topical application to the skin.

15. A formulation according to claim 14, for delivery of ozonated compounds primarily to the epidermis.

16. A formulation according to claim 14, for delivery of ozonated compounds primarily to the epidermis and papillary dermis.

17. A formulation according to claim 14, for delivery of ozonated compounds to the epidermis, papillary dermis and reticular dermis, but not to adipose tissue.

18. A cosmetic formulation according to any of claims 14 to 17.

19. A lip balm, moisturiser, facial, cleanser or anti- aging product, or massage oil comprising a formulation according to claim 14.

20. A lip balm according to claim 19, containing 1.0 - 2.0 %, preferably 1.5 - 1.9 %, preferably 1.72 % ozonated compounds.

21. A moisturiser according to claim 19, containing 2.0 - 3.0 %, preferably 2.3 - 2.8 %, preferably 2.59 % ozonated compounds.

22. A facial, cleanser or anti-aging product according to claim 19, containing 3.0 - 4.0 %, preferably 3.4 - 3.8 %, preferably 3.61 % ozonated compounds.

23. A massage oil according to claim 19, containing 4.0 — 5.0 %, preferably 4.3 — 4.7 %, preferably 4.50 % ozonated compounds.

24. Use of a formulation according to claim 14 as a lip balm, moisturiser, facial, cleanser or anti-aging product, or as a massage oil.

25. An oil according to any of claims 1 to 13 for use in therapy.

26. Use of an oil according to any of claims 1 to 13 for the manufacture of a medicament for use in the treatment or prophylaxis of a dermatological condition, disease or disorder.

27. Use according to claim 26 for the manufacture of a medicament for use in the treatment or prophylaxis of acne, psoriasis, eczema, skin cancer or a dermatological condition, disease or disorder associated with Type I diabetes.