AU772825B2

AU772825B2 - Sunscreen agent for oral administration

Info

Publication number: AU772825B2
Application number: AU72813/00A
Authority: AU
Inventors: Christine Gartner; Ulrike Heinrich; Wilhelm Stahl
Original assignee: Cognis Deutschland GmbH and Co KG
Current assignee: BASF Personal Care and Nutrition GmbH
Priority date: 1999-09-08
Filing date: 2000-08-30
Publication date: 2004-05-06
Anticipated expiration: 2020-08-30
Also published as: JP2003508485A; DK1210073T3; ATE254912T1; DE50004582D1; WO2001017519A1; EP1210073A1; ES2211597T3; DE19942774A1; AU7281300A; EP1210073B1

Abstract

The invention relates to preparations for oral administration, comprising a defined ratio of beta -carotene, lutein and lycopine . The invention also relates to methods for increasing the light protection factor of the skin and delaying the ageing process of the skin, in addition to the use of said preparations.

Description

WO 01/17519 PCT/EP00/08435 Sunscreen Agent for Oral Administration Field of the Invention This invention relates generally to orally administered sun protection preparations and more particularly to a mixture of 3-carotene, lutein and lycopene.

Prior Art Under the influence of the sun's rays, normal skin is pigmented by the formation of melanin. Exposure to long-wave UV-A light results in darkening of the melanins already present in the epidermis without any harmful effects while exposure to short-wave UV-B radiation results in the formation of new melanin. However, before the protective pigment can be formed, the skin is exposed to the effect of unfiltered radiation which can lead to reddening of the skin (erythema), inflammation of the skin (sunburn) or even to blisters, depending on the exposure time. The strain on the organism associated with such skin lesions, for example in connection with the distribution of histamines, can additionally lead to headache, lassitude, fever, heart and circulation problems and the like. In addition, long-term exposure can lead to cumulative DNA damage which can result in skin cancer. Consumers seeking to protect themselves against the harmful effects of the sun basically have two choices: first, they can protect the skin by topical application of cosmetic preparations containing UV protection factors, second they can increase the skin's own protection factor by oral application of suitable compounds.

European patent application EP 0 712 630 A2 (JBC Cosmetics) describes an orally administered preparation containing a carotinoid, a tocopherol, ascorbic acid and selenium. This preparation is intended to tan the skin and to prevent sun.allergies (photodermatoses). a-Carotene, 1-

I

WO 01/17519 PCT/EP00/08435 carotene and lycopene are used as the carotinoids in daily doses of 60 to 150 mg.

French patent application FR 2 698 268 Al (L'Or6al) describes a composition for oral administration to human beings which contains tyrosine and/or phenyl alanine, a copper salt and a mixture of vitamins.

Carotenes, vitamin E, niacin and vitamin.C may be used as the vitamins.

The carotenes mentioned include p- and y-carotene and lycopene which may be used in doses of 5 to 50 mg. The preparation is intended to protect the skin against the harmful effects of UV radiation.

Sun protection preparations for topical application where synthetic UV filters are replaced by substances of natural origin are described in EP 0 747 039 A2 (SA.FO.SA.). These sun protection preparations contain a mixture of amino acids, vitamins and/or provitamins, nucleoderivatives and vegetable extracts and may be used in the form of gels, creams or oils.

International patent application WO 97/47278 (Laboratoires Oenobiol.) claims a mixture for oral application containing at least one natural carotinoid with provitamin A character (either aor p-carotene), at least one natural carotinoid without provitamin A character (lycopene) and another carotinoid selected from the group consisting of zeaxanthin, cryptoxanthin and lutein, the ratio of to being 0.95:1 to 1:50. In Example 1, this application describes a composition of 2.86 mg p-carotene and 3 mg lycopene. The mixture also contains 0.07 mg lutein as a secondary component of the pcarotene source.

Accordingly, the prior art literature describes numerous oral preparations which are supposed to increase the skin's own sun protection factor. Most of these preparations are based on a- or p-carotene. Since studies have shown that the supplementation of p-carotene can increase I the incidence of lung cancer (ATBC Study, the New England Journal of Medicine, 1994, 330, 1029-1035 and CARET Study, G.S. Omenn et al, The New England Journal of Medicine, 1996, 334, 1150-1155), there is a need for a substitute'or partial substitute for p-carotene in known oral sun protection preparations.

Accordingly, the problem addressed by the present invention was to provide improved sun protection preparations for oral administration. More particularly, by comparison with known sun protection preparations, a proportion of a- or p-carotene would be replaced by other, at least equally effective substances. The requirements which these substitutes would be expected to satisfy would be stringent. Besides providing comparable or better protection against the sun, they would have to be toxicologically safe and easy to handle and formulate. In addition, the substitutes in question would preferably be substances of natural origin. Besides increasing the skin's own sun protection factor, the sun protection preparations provided by the invention would also delay ageing of the skin.

Description of the Invention According to an embodiment of the present invention, there is provided use of p-carotene, lutein and lycopene 20 in a ratio by weight of to to of for the production of preparations which are suitable for oral administration and which increase the sun protection factor of the skin.

According to a further embodiment of the present invention, there is provided use of p-carotene, lutein and lycopene in a ratio by weight of to to of 1:1:1 for the production of preparations which are suitable for oral administration and which delay the ageing process of the skin.

According to a further embodiment of the present invention, there is provided a 30 method of increasing the sun protection factor of the skin comprising orally administering: p-carotene, lutein and lycopene [I:\DayLib\LBC\Cognis]58681 Ospccidoc:gym in a ratio by weight of(a) to to of to a subject.

According to a further embodiment of the present invention, there is provided a method of delaying the ageing process of the skin comprising administering P-carotene, lutein and lycopene in a ratio by weight of(a) to to of 1:1:1 to a subject.

It has surprisingly been found that the oral administration of the preparations according to the invention increases the sun protection factor of the skin and at the same time delays ageing of the skin. The mixtures are toxicologically safe for oral administration and are easy to formulate. It has surprisingly been found that the mixture of these three particular ooo o* oo [I:\DayLib\LIBC\Cognis]586810speci.doc:gym WO 0 1/17519 PCT/EP00/08435 carotinoids in the claimed ratio to one another is particularly suitable for increasing the sun protection factor of the skin and for delaying the ageing process of the skin. In contrast to the mixtures of WO 97/47278, the mixtures according to the invention produce a distinctly improved increase in the sun protection factor of the skin.

3-Carotene H-C CH CH3 3 4 f3 carotene 7 3 9 11 13 15 6'1 2 6 15' 13' 11' 9' 7' 4 5 CH3 H3 3 p carotene p-Carotene is an 11x-unsaturated tetraterpene. The chemical skeleton consists of nine conjugated double bonds and two p-ionone ring structures at the ends of the molecule where the double bonds of the p-ionone system are in conjugation with the unsaturated system of the polyene chain. The double bonds may be in the trans position (trans-p-carotene, p,p-carotene, provitamin A) or in the cis position (for example 9-cis-p-carotene and 13cis-p-carotene). p-carotene in the context of the invention encompasses both the cis and the trans isomers of p-carotene. The p-carotene may be obtained both by extraction from vegetable sources (for example carrots and other vegetables, palm oil) or from animal materials, bacteria and/or algae (more particularly from the alga Dunaliella salina) and microbiologically or synthetically via vitamin A (retinol). It is particularly preferred to use p-carotene obtained by extraction from algae, more particularly by extraction from the alga Dunaliella salina which is commercially obtainable as Betatene®.

WO 01/17519 5 PCT/EP00/08435 Lutein Lutein in the context of the present invention includes both lutein itself [=(3R,3'R,6'R)-p,e-carotene-3,3'-diol;

C

4 0

H

56 0 2 MW 568.85] and the fatty acid esters of lutein. Suitable fatty acid esters are the esters of palmitic acid, myristic acid, stearic acid, lauric acid and oleic acid, the esters being both mono- and diesters and mixed forms (for example lutein myristyl palmitate).

OH

HO

lutein Lutein and its fatty acid esters may be obtained both by extraction from vegetable material (for example from varieties of Tagetes erecta (grass-of- Parnassus), stinging nettle leaves, lucern (for example alfalfa), palm oil), by extraction from animal material (for example egg yolk) and from bacteria or algae. It is particularly preferred to use lutein obtained by extraction from plants, more particularly lutein obtained by extraction from Tagetes erecta varieties which is commercially available as Xangold®.

Lycopene Lycopene in the context of the present invention includes both the all trans isomer (,y-carotene, C 40

H

5 6 MW 536.85) and the cis isomers (such as, for example, 5-cis-, 9-cis-, 13-cis- and 15-cis-lycopene). Lycopene can be obtained by extraction from plants (tomato (Solanum lycopersicum), rose hip and other fruits, chanterelles (Cantharellus cibarius)) and by extraction from animal material. Lycopene can also be obtained by synthesis or extraction from microorganisms (fermentative protection). It is I WO 01/17519 PCT/EP00/08435 particularly preferred to use lycopene obtained by fermentation or by extraction from plants.

lycopene The ratio of the individual components to one another is crucial to the invention. It has surprisingly been found that, where components and are present in a ratio of to to of 1 the preparations obtained are distinguished from known preparations by a particularly effective increase in the sun protection factor of the skin.

Particularly preferred preparations are those with a ratio of to to (c) of 1 (0.5 1.0) (0.5 more particularly 1.0 1.0: 1.0, and a ratio of 1 0.5: 0.5 and 1: 0.75 0.75.

Carriers suitable for oral application A key component of the preparations according to the invention is the carrier suitable for oral application. It is intended on the one hand to dissolve or disperse the carotinoid mixture according to the invention. In addition, it preferably supports the absorption of the carotinoids from the gastrointestinal tract. In principle, suitable carriers are any substances which perform these functions and which are toxicologically safe.

Examples of suitable carriers are edible oils (particularly soybean oil), such as vegetable and fish oils which may optionally be partly hydrogenated, and carriers based on animal products, for example gelatine. Other suitable carrier materials are, for example, gum arabic, sucrose, lipids, mono- and diglycerides and maltodextrins. Where water is used as the carrier material, it is standard practice to use a suitable emulsifier (for example lecithins, sorbitan monolaurate).

WO 01 /17519 PCT/EP00/08435 The preparations may be orally administered, for example, as solutions, oils, emulsions, suspensions or dispersions. Suitable carrier forms are, for example, capsules or tablets. The preparations according to the invention are normally present in the form of soft gelatine capsules.

The preparations according to the invention are normally prepared by preparing a mixture of p-carotene, lutein and lycopene and then encapsulating the mixture thus prepared together with the carrier material.

The present invention includes the observation that the preparations according to the invention may be added to foods and that the foods thus enriched may be used as carriers for oral administration.

The present invention also includes the observation that typical antioxidants such as, for example, ascorbyl palmitate (E 304), mixed tocopherols (E 306), citric acid (E 330) or L-ascorbic acid (E 300) may be added to the preparations according to the invention.

In a preferred embodiment of the invention, the preparations according to the invention contain at least one other substance selected from the group consisting of a-carotene, astaxanthin, a-cryptoxanthin, pcryptoxanthin, zeaxanthin, phytoene, phytofluene, y-carotene and neurosporin.

The systematic names of the substances mentioned are as follows: a-carotene p,s-carotene astaxanthin (3S,3'S)-3,3'-dihydroxy-p,p-carotene-4,4'-dione a-cryptoxanthin (3R)-p,e-carotene-3-ol P-cryptoxanthin (3R)-p,p-carotene-3-ol zeaxanthin (3R,3'R)-p,p-carotene-3,3'-diol) phytoene 7,8,11,12,7',8',11',12'-octahydro-y,W-carotene phytofluene 7,8,11,12,7',8'-hexahydro-y,W-carotene y-carotene P,w-carotene neurosporin 7,8-y,-carotene.

WO 01/17519 PCT/EP00/08435 It is particularly preferred to use a-carotene.

It has surprisingly been found that the sun protection factor of the skin is increased by the oral administration of preparations containing 3carotene, lutein and lycopene in a ratio by weight of to to (c) of 1 (0.5 1.5) (0.5 1.5) in a carrier suitable for oral administration.

Accordingly, the present invention also relates to a process for increasing the sun protection factor of human skin, characterized in that the preparations according to the invention are orally administered.

The sun protection factor of the skin may be determined by any of the methods known to the expert such as, for example, determination of the minimum erythema activity (MED) as described by COLIPA. Other methods include determination of the melanin content and the concentration of the carotinoids in the skin by reflection spectrophotometry and/or HPLC and chromometric determination of skin color b and L values). A description of these methods can be found, for example, in Biochemistry and Molecular Biology International, 42, No. 5, 1997, pp.

1023-1033.

The duration of supplementation is normally determined by the existing sun protection factor of the skin and by the individually very different absorption capacity. It may be carried out for several days, several weeks or even for several months or years. Because the preparations according to the invention are toxicologically safe, supplementation may even be carried out indefinitely, as desirable for example in people exposed much more than normal UV radiation.

It has surprisingly been found that the ageing process of human skin is delayed by the oral administration of preparations containing and in a ratio by weight of 1 (0.5 1.5) (0.5 1.5) in a carrier suitable for oral administration. Accordingly, the present invention also relates to a process for delaying the ageing process of the skin, characterized in that the preparations according to the invention are orally administered.

I I WO 01/17519 PCT/EP00/08435 The duration of supplementation is normally determined by the state of ageing of the skin and by the individually very different absorption capacity. It may be carried out for several days, several weeks or even for several months or years. Because the preparations according to the invention are toxicologically safe, supplementation may even be carried out indefinitely.

The quantity of components and expressed as a daily dose is normally between 1 and 40 mg per component, with the proviso that the ratio of to to is 1 (0.5 1.5) (0.5 Quantities of 2 to 25 mg per component and more particularly 5 to 10 mg per component are preferred. The preparations according to the invention may be administered as a single daily dose or as several doses distributed over a day.

The present invention also relates to the use of the orally administered preparations claimed in claim 1 for increasing the sun protection factor of human skin.

The present invention also relates to the use of the orally administered preparations claimed in claim 1 for delaying the ageing process of human skin.

Examples The carotinoid absorption and photoprotection studies were carried out using a panel of 36 volunteers with healthy skin of light typed II (Fitzpatrick Pathak test). The starting values for each volunteer were determined at the beginning of the 12-week study. An interim study was conducted after 6 weeks and the final study after 12 weeks. The volunteers were divided into three groups of twelve who received the following daily doses: 1st group: 25 mg Betatene® (corresponds to 24 mg 3-carotene) WO 0 1/17519 PCT/EP00/08435 2nd group: 8.3 mg Betatene@ (corresponds to 8 mg p-carotene), 8 mg lycopene, 8 mg lutein (Xangold®) 3rd group: placebo capsules.

The carotinoids were administered in soft gelatine capsules with 140 mg soybean oil.

The concentration of p-carotene, lycopene and lutein in the skin was determined by reflection spectrometry which was carried out on an area of 1 cm 2 of the forehead, the back of the hand, the palm of the hand, the inside of the lower arm and the back. The change in color of the skin during supplementation was differentiated by a Minolta chromameter a, b system) into reddening of the skin (a values), yellow component (b values) and lightness of the skin (L values). The concentration of pcarotene, lycopene and lutein in the serum was determined by highpressure liquid chromatography (HPLC).

The results are set out in Table 1 and represent the average values for the volunteer panel on completion of the study. The photoprotective value is expressed relative to the blank value no addition of carotinoids, group 3).

Table 1 Photoprotective effect Group Carotinoids (daily dose) Photoprotection 1 p-carotene (24 mg) 200 2 p-carotene (8 mg), lycopene (8 mg) 270 and lutein (8 mg) 3 Control group with no carotinoids 100 WO 01/17519 11 PCT/EP00/08435 It can be seen that the administration of the Betatene mixture (pcarotene) doubles the photoprotection of the skin (group 2) in relation to the blank value (group Where mixtures of Betatene (p-carotene) and lutein and lycopene are used, a distinct increase in photoprotection is obtained (group The group 2 results clearly show that this effect is not an additive one because the same quantity of p-carotene (group 3) fails to achieve this protective effect.

1

Claims

1. The use of P-carotene, lutein and lycopene in a ratio by weight of to to of for the production of preparations which are suitable for oral administration and which increase the sun protection factor of the skin.

2. The use of p-carotene, lutein and lycopene in a ratio by weight of to to of 1:1:1 for the production of preparations which are suitable for oral administration and which delay the ageing process of the skin.

3. A method of increasing the sun protection factor of the skin comprising orally administering: P-carotene, lutein and lycopene 20 in a ratio by weight of(a) to to of to a subject. S4. A method of delaying the ageing process of the skin comprising administering p-carotene, lutein and lycopene in a ratio by weight of to to of 1:1:1 to a subject.

I

5. Use of P-carotene, lutein and lycopene substantially as hereinbefore described S:"with reference to any one of the examples.

6. A method of increasing the sun protection factor of the skin comprising the go• steps substantially as herein described. [I:\DayLib\LIBC\Cognis]58681 Ospeci.doc:gym

7. A method of delaying the ageing process of the skin comprising the steps substantially as herein described. Dated 18 February, 2004 Cognis Deutschland GmbH Co KG Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 0* S 0 0 0* S S S 0 55 0 S S 00 0 0S 0 505 S 0555 0555 S *SSS S. 0 OS SO 0555 S 0000 5005 S *SSS 55 0* [I:\DayLib\LIBC\Cogn is] 5868 1Ospeci.doc: gym