WO2010112071A1

WO2010112071A1 - Combination of astaxanthin, antioxidants and colouring agents with sunscreen effect to be administered orally

Info

Publication number: WO2010112071A1
Application number: PCT/EP2009/053893
Authority: WO
Inventors: Mauro Mantovani; Stefano Valier
Original assignee: Phf S.A.
Priority date: 2009-04-01
Filing date: 2009-04-01
Publication date: 2010-10-07

Abstract

The present invention relates to a pharmaceutical or dietary composition containing Astaxanthin and several antioxidants with sunscreen effect and being characterized by oral administration. The present invention relates to a formulation where the stability as well as the biological action of Astaxanthin are synergistically improved by the presence of other antioxidants, like carotenoids, ascorbic acid, resveratrol, tocopherol, lycopene and bixine.

Description

COMBINATION OF ASTAXANTHIN, ANTIOXIDANTS AND COLOURING AGENTS WITH SUNSCREEN EFFECT TO BE ADMINISTERED ORALLY Field of the invention

The present invention relates to a pharmaceutical or dietary composition containing Astaxanthin and several antioxidants with sunscreen effect and being characterized by oral administration. Background art

Astaxanthin is a carotenoid. It belongs to a larger class of phytochemicals known as terpenes. It is classified as a xanthophyll, which means "yellow leaves". Like many carotenoids, it is a colorful, fat/oil-soluble pigment. Astaxanthin can be found in microalgae, yeast, salmon, trout, krill, shrimp, crayfish, crustaceans, and the feathers of some birds.

Astaxanthin, unlike some carotenoids, does not convert to Vitamin A (retinol) in the human body. Too much Vitamin A is toxic for a human, but Astaxanthin is not. However, it is a powerful antioxidant; it is 10 times more active than other carotenoids.

While Astaxanthin is a natural nutritional component, it can be found as a food supplement. The supplement is intended for human, animal and aquaculture consumption. The commercial production of Astaxanthin comes from both natural and synthetic sources. The FDA approved Astaxanthin as a food coloring (or color additive) for specific uses in animal and fish foods. The European Union considers it food dye within the E number system, Elβlj. The primary use of synthetic Astaxanthin today is as an animal feed additive to impart coloration, this includes farm-raised salmon and egg yolks.

Currently, the primary use for humans is as a food supplement. Research shows that due to its potent antioxidant activity, it may be beneficial in cardiovascular, immune, inflammatory and neurodegenerative diseases. Research results confirmed that it protects body tissues from oxidative damage. It also crosses the blood-brain barrier, which makes it available to the eye, brain and central nervous system to alleviate oxidative stress that contributes to ocular, and neurodegenerative diseases such as glaucoma and Alzheimer's disease. It is also reported in different scientific publications that Astaxanthin is endowed with a certain protective action against the UV damage on the skin .

The normal daily intake of Astaxanthin is 4 mg for all the applications.

The colouring agent used in the formulation is Annatto extract (Bixa Orellana L.), which is used to colour food products, such as cheeses, fish and salad oil. Sold as a paste or powder for culinary use, mainly as a colour, it is known as "achiote, " "annatto" or "pimentao doce". Annatto is growing in popularity as a natural alternative to synthetic food colouring compounds .

The achiote has long been used by American Indians to make body paint, especially for the lips, which is the origin of the plant's nickname, ^λlipstick tree' . Various indigenous groups paint their hair and bodies with the pulp to repel insects and protect from sunburn.

The main disadvantage of Astaxanthin is that it is sensible to sun exposure, storage under daylight, oxidation by air exposure and at high temperatures, which cause its degradation to astacene. This degradation is caused by a relatively low activity of the product, in certain stress conditions.

Moreover, in the case of use as protective agent preventing sun exposure damages, there is evidence that the treatment gives a result after at least 2 weeks of administration of Astaxanthin 4 mg per day. So, people have to start the treatment some time before the sun exposure period that normally happens during the summer vacations. This fact represents a compliance problem, because people taking Astaxanthin alone don't see and feel any benefit in the pre-treatment period. This may reduce the compliance of people under treatment causing discontinuation or not regular product intake. Description of the invention

The present invention relates to a formulation where the stability of Astaxanthin is improved by the presence of other antioxidants, like carotenoids, ascorbic acid, resveratrol, tocopherol, lycopene and bixine.

The second effect of the combination of all these active compounds was unexpected and it is synergic with Astaxanthin, giving to the mixture an antioxidant potential which is higher than summing up the effects of the single components. This effect is particularly evident in preventing the skin irritation from sun exposure . Also the food colouring agent (Annatto extract - Bixa Orellana L.) is added to the mixture for the purpose of increasing the compliance of human subjects, giving a bronze colour, with a final result of better and deeper tanning of the skin. This induce the subject to carry out regularly the treatment prescribed. Also the antioxidant effect of Bixa Orellana extract is useful to increase the sunscreen effect of the formula described in the present invention . Moreover, it has been demonstrated that this mixture has a sunscreen effect which is typical of a topic dermal formulation, that in standard cases is higher than the effect achieved with oral preparations of the prior art. The inventive oral composition comprises Astaxanthin together with a synergistically effective amount of at least three auxiliary components selected from Red Orange (Citrus aurantium dulcis) extract, Maritime Pine (Pinus pineaster) extract, carotenoids, ascorbic acid, resveratrol, alpha-tocopherol, lycopene, selenium L- methionine, L-glutathione and bixin. The term "synergistically effective amount" means an amount of active principle that is biologically effective and that is able to produce a synergistic effect if administered together with the other components of the composition . In one embodiment, the said three auxiliary components are bixin, Maritime Pine (Pinus pineaster) extract and Red Orange (Citrus aurantium dulcis) extract. In another embodiment, the inventive composition comprises four auxiliary components. In a particular embodiment, these four components are bixin, Maritime Pine (Pinus pineaster) extract, Red Orange (Citrus aurantium dulcis) extract and resveratrol.

In another embodiment, the inventive composition comprises five auxiliary components. In a particular embodiment, these five auxiliary components are bixin, Maritime Pine (Pinus pineaster) extract, Red Orange (Citrus aurantium dulcis) extract, resveratrol and carotenoids .

In another embodiment, the inventive composition comprises six auxiliary components. In a particular embodiment, these six auxiliary components are bixin, Maritime Pine (Pinus pineaster) extract, Red Orange (Citrus aurantium dulcis) extract, resveratrol, carotenoids and lycopene. In one embodiment, a 10 wt% Red Orange (Citrus aurantium dulcis) extract is used.

In one embodiment, a 15 wt% Red Grape (Vitis vinifera) resveratrol extract is used to supply resveratrol. In one embodiment, a 20 wt% Natural mixed carotenoids complex concentrate, extracted from palm fruits (Elaeis guineensis) , is used.

In one embodiment, a 6 wt% Natural lycopene complex oleoresin is used.

When Red Orange (Citrus aurantium dulcis) extract is used, it is present in amounts ranging from 6 to 10 mg, or from 7 to 9 mg, or about 8 mg of 10 wt% extract per mg of astaxanthin or in an equivalent amount thereof. When resveratrol is used it is present in amounts ranging from 3 to 7 mg, or 4 to 6 mg, or about 5 mg of 15 wt% Red Grape (Vitis vinifera) resveratrol extract per mg of astaxanthin, or in an equivalent amount thereof. When Maritime Pine (Pinus pineaster) extract is used, it is present in amounts ranging from 1 to 5 mg, or 2 to 4 mg, or about 3 mg of Maritime Pine (Pinus pineaster) extract per mg of astaxanthin, or in an equivalent amount thereof.

When carotenoids are used, they are present in amounts ranging from 3 to 7 mg, or 4 to 6 mg, or about 5 mg of 20 wt% Natural mixed carotenoids complex concentrate per mg of astaxanthin, or in an equivalent amount thereof. When bixin is used, it is present in amounts ranging from 25 to 35 mg, or 27 to 33 mg, or about 30 mg of bixin per mg of astaxanthin, or in an equivalent amount thereof. When lycopene is used, it is present in amounts ranging from 3 to 7 mg, or 4 to 6 mg, or about 5 mg of 6 wt% Natural lycopene complex oleoresin per mg of astaxanthin, or in an equivalent amount thereof.

The term "equivalent amount" as used herein above means the same amount of active principle present in a different formulation or as a pure product corresponding to the amount of the formulation described above. "Formulation" means any extract, complex, concentrate or the like in which the active principle of the auxiliary component may be available. For example, if a 20 wt% Red Orange (Citrus aurantium dulcis) extract is used instead of the above disclosed 10 wt% extract, 3 to 5 mg of such 20 wt% extract per mg of astaxanthin will be an equivalent amount of this auxiliary component. In one embodiment, the inventive composition may also comprise : - ascorbic acid (vitamin C) in amounts ranging from 20 to 40 mg per mg of astaxanthin, and/or

- alfa-tocopherol (vitamin E) in amounts ranging from 1 to 9 mg per mg of astaxanthin, and/or

- Selenium L-Methionine in amounts ranging from 1 to 9 mg per mg of astaxanthin, and/or

- L-Glutathione in amounts ranging from 1 to 7 mg per mg of astaxanthin.

Astaxanthin can be administered in a daily amount ranging from 0.5 to 4 mg, in order to obtain a biological effect as antioxidant with sunscreen effect.

A method of treating or preventing an oxidative stress to a subject in need thereof, the said method comprising administering an effective dosage of the composition as disclosed above, is also provided by the present invention.

The inventive composition may be formulated in any way suitable for oral administration, such as those described in Remington's Pharmaceutical Sciences H a n d b o o k , M a c k P u b . C o . , N . Y . , USA, 17th edition, 1985. For example, the oral composition of the invention can be formulated as soft gel capsules, tablets, pills, syrups, elisirs and any other suitable form. EXPERIMENTAL PART

Herein below it is described an example of formulation (soft gel capsules) . The results obtained in clinical studies are also shown.

Example of preparation

The typical composition of the formulation is the following (1 soft gel capsule contains):

• Bixin Oleoresin 60 mg

• Vitamin C 60 mg

• Rose^® 16 mg

• Grape' ox^® 10 mg

• Caromin^® 10 mg

• Maxopene^® 10 mg

• Vitamin E 10 mg

• Selenium L-Methionine 10 mg

• L-Glutathione 8 mg

• Pycnogenol^® 6 mg • Astaxanthin 2 mg

Rose^® = Red Orange (Citrus aurantium dulcis) extract 10%

Grape'ox^® = Red Grape (Vitis vinifera) resveratrol extract 15% Caromin^® = Natural mixed carotenoids complex 20% concentrate, extracted from palm fruits (Elaeis guineensis)

Maxopene^® = Natural lycopene complex 6% oleoresin Pycnogenol^® = Maritime pine (Pimus pinaster) extract

Clinical studies

Clinical study 1: Evaluation of skin pigmentation effect (Melanin Index) :

• Ten subjects; • Treatment: 1 cps/day for 15 days;

• Instrument: MEXAMETER colorimetric probe, Courage and Khazaka Electronic;

• Evaluation: skin pigmentation increase on forearm, back and thigh. Clinical study 2: Evaluation of improved Minimal Erithemal Dose (MED) :

• Ten subjects;

• Treatment: 1 cps/day for 15 days;

• Instrument: SOLAR Multiportal Simulator, Solar Light;

• Evaluation: Minimal Erythemal Dose (MED) on back;

Clinical study 3: Evaluation of antioxidant capacity (FRAP) and lipid peroxidation (LPO) of the skin: • Ten subjects;

• Treatment: 1 cps/day for 15 and 30 days; • Instrument: Corneofix dermal patch;

• Evaluation: degree of lipid peroxidation (LPO) and antioxidant capacity (FRAP) of the skin.

Results S kin p igment at i on i s increa sed a f ter supplementation. The melanine index revealed by a colorimetric probe, is enhanced of 15,7% as average.

The supplementation increases Minimal Erithemal Dose (MED) , after exposure to a standard solar multiportal simulator, of 30, 4% and the consequence is a less sensitivity to UVB irradiation.

These data demonstrate the utility and industrial application of the present invention.

This invention can be used for pharmaceutical use or as a dietary supplement and in particular as an antioxidant with a sunscreen effect.

Claims

1. An oral composition comprising Astaxanthin together with a synergistically effective amount of at least three auxiliary components selected from Red Orange Citrus aurantium dulcis extract,

Maritime Pine Pinus pineaster extract, carotenoids, ascorbic acid, resveratrol, alpha- tocopherol, lycopene, selenium L-methionine, L- glutathione and bixin.

2. The oral composition of claim 1, wherein the said three auxiliary components are bixin, Maritime Pine Pinus pineaster extract and Red Orange Citrus aurantium dulcis extract.

3. The oral composition of claim 1, comprising four auxiliary components, the said four components being bixin, Maritime Pine Pinus pineaster extract, Red Orange Citrus aurantium dulcis extract and resveratrol.

4. The oral composition of claim 1, comprising five auxiliary components, the said five auxiliary components being bixin, Maritime Pine Pinus pineaster extract, Red Orange Citrus aurantium dulcis extract, resveratrol and carotenoids.

5. The oral composition of claim 1, comprising six auxiliary components, the said six auxiliary components being bixin, Maritime Pine Pinus pineaster extract, Red Orange Citrus aurantium dulcis extract, resveratrol, carotenoids and lycopene .

6. The oral composition according to any of claims 1 to 5, wherein the said Red Orange Citrus aurantium dulcis extract is a 10 wt% extract.

7. The oral composition according to any of claims 1 to 6, wherein the said resveratrol is supplied as 15 wt% Red Grape (Vitis vinifera) resveratrol extract.

8. The oral composition according to any of claims 1 to 7, wherein the said carotenoids are supplied as 20 wt% Natural mixed carotenoids complex concentrate, extracted from palm fruits Elaeis guineensis .

9. The oral composition according to any of claims from 1 to 8, wherein the said lycopene is supplied as 6 wt% Natural lycopene complex oleoresin .

10. The oral composition according to any of claims 1 to 9, wherein if Red Orange Citrus aurantium dulcis extract is used, it is in amounts ranging from 6 to 10 mg, or from 7 to 9 mg, or about 8 mg of 10 wt% extract per mg of astaxanthin or in an equivalent amount thereof.

11. The oral composition according to any of claims 1 to 10, wherein if resveratrol is used, it is in amounts ranging from 3 to 7 mg, or from 4 to 6 mg, or about 5 mg of 15 wt% Red Grape Vitis vinifera resveratrol extract per mg of astaxanthin, or in an equivalent amount thereof.

12. The oral composition according to any of claims from 1 to 11, wherein if Maritime Pine Pinus pineaster extract is used, it i s in amounts ranging from 1 to 5 mg, or from 2 to 4 mg, or about 3 mg of Maritime Pine (Pinus pineaster) extract per mg of astaxanthin, or in an equivalent amount thereof.

13. The oral composition according to any of claims from 1 to 12, wherein if carotenoids are used, they are in amounts ranging from 3 to 7 mg, or from 4 to 6 mg, or about 5 mg of 20 wt% Natural mixed carotenoids complex concentrate per mg of astaxanthin, or in an equivalent amount thereof.

14. The oral composition according to any of claims from 1 to 13, wherein if bixin is used, it is in amounts ranging from 25 to 35 mg, or from 27 to 33 mg, or about 30 mg of bixin per mg of astaxanthin, or in an equivalent amount thereof.

15. The oral composition according to any of claims from 1 to 14, wherein if lycopene is used, it is in amounts ranging from 3 to 7 mg, or from 4 to 6 mg, or about 5 mg of 6 wt% Natural lycopene complex oleoresin per mg of astaxanthin, or in an equivalent amount thereof.

16. The oral composition according to any of claims from 1 to 15, further comprising:

- ascorbic acid (vitamin C) in amounts ranging from 20 to 40 mg per mg of astaxanthin, and/or

- alpha-tocopherol (vitamin E) in amounts ranging from 1 to 9 mg per mg of astaxanthin, and/or

- L-Glutathione in amounts ranging from 1 to 7 mg per mg of astaxanthin.

17. The oral composition according to any of claims from 1 to 16, in the form of soft gel capsules, tablets, pills, syrups or elisirs.

18. The oral composition according to any of claims from 1 to 17, containing a daily dosage of Astaxanthin in the range from 0.5 to 4 mg.

19. The use of the oral composition according to any of claims from 1 to 18 for use as a dietary supplement .

20. The oral composition according to any of claims from 1 to 18 for use as antioxidant with a sunscreen effect.