ES2351571B1 - USE OF A COMPOSITION CONTAINING AN EXTRACT FROM A GRAMMINE PLANT FOR THE PREVENTION OF CUTANEOUS INJURIES ORIGINATED BY ULTRAVIOLET RADIATION - Google Patents

Abstract

Use of a topical pharmacological composition containing an extract of a grass plant of the Deschampsia, Ballica or Festuca family, for its application to the prevention or treatment of skin lesions, especially non-melanoma skin cancer, generated by exposure to UV radiation

Description

Use of a composition that contains an extract of a grass plant for the prevention of skin lesions caused by ultraviolet radiation.

Technical field

The present invention refers to the use of a plant belonging to the grass family from the Antarctic continent, or from areas with cold climates similar to those of the Antarctic, for the prevention of skin lesions of human skin generated by the harmful effects of radiation exposure UV

Prior art

It is well known that the skin, subjected to solar radiation, suffers certain damages. The main component of solar radiation, which has the greatest potential to cause damage to the skin, is ultraviolet (UV) radiation, which can be of three types: UVA (315-400 nm), UVB (290-315 nm) yUVC (240-290 nm). UVA radiation has a greater penetration, up to the reticular dermis, and causes photosensitivity and premature photoaging, and also has an important role together with UVB in carcinogenesis. The damaging effects of UVB radiation are shortened and mainly affect the epidermis, being the main cause of skin burns and, by itself, causes skin cancer. Finally, UVC is the most harmful, but it does not reach the surface of the earth when it is retained by the ozone layer. However, the progressive decrease of this layer is causing a notable increase in skin lesions associated with excess sun exposure and that are closely related to skin cancer.

One of the skin lesions with the highest incidence in recent years is nonmelanoma skin cancer (CCNM) (see “UV-induced skin damage” Toxicology 2003, 189, 21-39 by M. Ichihashi et al; “Management of nonmelanoma skin cancer ”Nature Clin. Prac. 2007, 4, 462-469 by JA Neville et al.). This type of skin cancer is the most frequent and constitutes 20% of all those diagnosed in man. The most common epithelial tumors are basal cell carcinomas (CBCs; it represents 75% of all CCNM) and squamous cell carcinomas (SCCs), whose incidence in the Caucasian population is high and increases every year due to exposure to saline. Actinic keratosis (QA), also known as solar keratosis, is the premalignant lesion that is most frequently detected in adult skin exposed chronically to UVA / UVB radiation. For example, in Australia, 40-50% of the population aged over 40 years presents actinic keratosis. Between 5% and 20% of these lesions can cause carcinomas of superficial squamous cells. Many of the CBCs and of the CCEs that are discovered early are treated successfully with conventional invasive pharmacological intervention therapies: expeller surgery, radiotherapy, micrograph surgery, and, in recent years, also photodynamic therapy (“Management of nonmelanoma skin cancer” Nature Clin. Prac. 2007, 4, 462-469 of JA Neville et al .; "Current modalities and new advances in the treatment of basal cell carcinoma" Int. J. Dermatol. 2006, 45, 489-498 by RI Ceilley et al.; "Actinickeratosis" Int.J. Dermatol. 2007, 46, 895-904 of R. Rossi et al.).

In order to protect the skin against these harmful effects of radiation, numerous solar filters of diverse chemical natures and varied physical and chemical properties have been described. These compounds ensure primary protection. However, the absorption of UV radiation by the fi lters is never total. There is, therefore, a residual amount of energy radiations that reach the skin. Thus, the solar filters attenuate the damage caused to the skin without suppressing them completely.

The notable increase in skin lesions that is occurring in recent years requires the need to develop new compounds that protect sun exposure, both short and long term, in order to prevent skin lesions.

The applicant firm has discovered that the topical application of a plant belonging to the grass family (Deschampsia antarctica) on the skin prevents skin lesions, including nonmelanoma skin cancer.

The photoprotective activity of the extract of Deschampsia antarctica is something already known, since patent nº 2009/000050 describes a new skin photoprotection agent against UVA (I and II) and UVB radiation containing said extract. However, the use of this extract for the purpose of preventing skin lesions such as non-melanoma skin cancer caused by UV radiation has not been described so far.

Thus, the present invention aims at the use of a composition for the prevention of skin lesions caused by UV radiation comprising an extract of a grass from the Antarctic continent, such as Antarctica Deschampsia, or grasses that can be grown in climates Colds similar to those of the Antarctic continent, such as the Ballica andFestucau grasses other than the Deschampsia family; distilled water and a conventional additive excipient used to obtain a formulation in the form of cream, gel, or liquid such as lotions, oils, suspensions or topical application ointments on the skin.

Description of the invention

The present invention is based on the use of preventive properties and skin lesions of an extract of a plant belonging to the grass family, such as Deschampsia, Ballica and Festuca, for its application in the prevention or treatment of skin lesions in both humans and animals, especially nonmelanoma skin cancer.

From the plant extract, plan a pharmaceutical pharmaceutical composition. Optionally, this composition may have other components such as antioxidants, physical filters, chemical filters, tanning agents, humectants, etc.

An extract of Deschampsia Antarctica (DA), which is presented in brown powder, is kept in the dark, in an airtight container with silica to prevent hydration and at a temperature of 4 ° C until use.

From an extract of the extract, a topical application is prepared, whose concentration of extract would vary between 150 mg / ml and 500 mg / ml, preferably 300 mg / ml.

A composition is prepared, which from now on we will call EADA (aqueous DA extract), with a concentration of 300mg / ml of AD extract. For the purpose of dissolving said extract in distilled water and subsequently in the inert Carbopol in proportion 3: 7.

Once said composition was prepared, different tests were performed in mice to verify its preventive effect of skin lesions caused by exposure to UV radiation.

Effect of EADA on the skin of mice (SKH-1) when applying UV radiation

The mouse model chosen “hairless Mouse” (SHK-1) is the most frequently used for studies of UV-induced carcinogenesis (see: “Dependenceofskin cancer inductionbyultraviolet irradiationofalbino hairless mice.” Cancer Res. 1993, 53, 53-60 deF.R. from Gruijl et al. and "UV-induces skin cancer in a hairless Mouse model." Bioessays. 1993,17,651-660deF.R.de Gruijl; PDForbes et al.). In this mouse model, UV radiation causes lesions similar to actinic keratoses after several weeks of irradiation and subsequently squamous cell carcinomas. The time required for the development of such lesions varies depending on the spectrum of the source of irradiation, the frequency of exposure and the dose used.In general, histological studies show that small papillomatous lesions (less than 4 mm) are actinic keratoses, while larger ones are squamous cell carcinomas. UV radiation does not generate melanomas or basal cell carcinomas in this animal model, a fact that the cause is unknown.

In order to carry out the study, 72 female SHK-1 mice were used, about 25-30g body weight and about 67 weeks old at the beginning of the trial.

The animals were distributed in groups of 6 animals per cage and maintained at a temperature at which the temperature was 22 ° C and their relative humidity between 50% and 75%, values that were controlled at all times and with 12-hour light / dark cycles. The animals received food and water ad libitum during the experimental time.

Each mouse received 25 µl of the EADA solution per 1.5 cm2 of the dorsal surface, or only of 50% diluted Carbopol in distilled water (v: v) (vehicle) by direct application on the skin.

The following groups of mice were made, each consisting of 12 animals, as indicated below in Table 1:

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Group 1: Controls without treating (mouse without treating with EADA and without subsequent irradiation with UV)

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Group 2: UV control (mice exposed only to UV light)

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Group 3: EADA + UV (subject to topical application of EADA and subsequent irradiation with UV)

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Group 4: SinelextractodeDA + UV vehicle (subject to topical application of the vehicle and ADtractor and subsequent irradiation with UV light)

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Group 5: EADA control (subject to topical application of EADA, without subsequent irradiation with UV light)

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Group 6: vehicle control without EADA (subject to topical application of the vehicle without EADA and without subsequent irradiation with UV light)

TABLE 1

Distribution of animals in the different experimental groups. * EADA was prepared in the vehicle at a concentration of 300 mg / ml. ** Carbopol inert gel

The mice were irradiated with a set of 6 lamps of UV according to the standardized protocol for an intracutaneous stop produced by chronic exposure to UV radiation (see: "Chronic Photodamage in Skin of Mast Cell-de fi cient Mice." Photochem. Photodamage. 1999, 70, 246-253 by S. González et al.).

The emission spectrum of the lamp assembly is shown in Fig. 1 The integrated power of the lamp group (radiance: 3.1 mW / cm2) was measured by the company Iberlélite S.A. using a specific spectrograph and source (Shamrck SR-163; EMCCD Newton, Power Meter UP19K).

The distance of the lamps to the mouse skin is approximately 15 cm and the daily dose received by each mouse subjected to UV was about 160 mJ / cm2 (Total Spectrum Energy), applied for 3-4 days per week.

In order to prepare the animals for the test, the mice of the corresponding experimental groups (groups 3-6) received topically EADA, or only the vehicle once a day (10:00 am, morning application ) during the first week of experimentation. Subsequently, the animals received the morning application of the vehicle 3-4 times a week and six hours later, the source of irradiation of the UV light was exposed (16: 00h, application of the early afternoon). The mice were subjected to UV light until most of the group 2 (control UV) showed papillomatous lesions or carcinomas of a size equal to 0.15-0.2 cm in diameter. This took place at 21 weeks of exposure to UV light, after each animal had accumulated a total UV dose of approximately 11,760 mJ / cm2.

Once the mice developed the tumors, the UV exposure sessions were suspended and the mice were kept for 4 more weeks, without treatment, until sacrifice (25 weeks after starting the experiment). All animals were sacrificed by CO2.

The evaluation of the skin damage generated in the mice was evaluated by carrying out a photographic study to show the effects of EADA, in relation to the UV exposure and through the analysis of the clinical characteristics of the skin. In the photographic study, the appearance of the skin, the time of the appearance of the tumors and the number and size of the tumors were mainly observed. For the estimation of the number and size of the tumors, only those located on the back of the animal, in the treated regions have been taken into account, while they have not been accounted for those that appeared in other positions (head, neck, lateral lateral regions of the trunk). Each animal showed biopsies of the dorsal skin, from the lower middle areas, separating the tumors.

On the other hand, statistical studies were carried out using the SPSS package, selecting different types of test according to the variables studied (type of treatment and number and size of lesions) and the sample size. Selected tests: kruskal-WallisyUMann-Whitney for the analysis and size and number of Pearson-squared lesions to determine the possible relationship with the treatment type (Control, vehicle, UV, EADA + UV, vehicle + UV).

Results

Table 2 shows the results obtained from the evaluations carried out on the skin of the mice of all the groups with specific times (5,10,18 and 21) weeks of starting the trial.

TABLE 2

Clinical analysis of the general state of the skin of the experimental groups and evolution of lesions induced by UV light in the different experimental groups. At each moment, the evaluations were carried out by three different people

Table 3 also shows the results at the end of the experimentation, that is, 25 weeks after the beginning of it. In this table we can observe the total number of papillomatous lesions with a diameter greater than 0.15 cm in each experimental group at the time of the evaluation, as well as the number of mice with tumors in relation to the total number of mice, indicated in brackets.

TABLE 3

Total number of papillomatous lesions larger than 0.15 cm in diameter present in each experimental group at the time of evaluation (10, 18, 21 and 25). In parentheses, the number of mice with tumors is recorded in relation to the total number of mice. A, b Animals (1 or 2 respectively) that have been sacrificed 21 weeks after starting the trial because they presented tumors larger than 0.5 cm in diameter.

The mice of the control groups that were not exposed to UV light (groups 1,5 and 6) presented an excellent cutaneous state both during the experimentation, where their skin was flushed, and at the end of it (Table 3), which indicated that neither the EADAni the vehicle (Carbopol + water) caused visible changes in the skin of the animals. It should be noted, however, the presence of a solid tumor located on the right side of the animal and in a caudalyventral position.

However, skin alterations were observed in animals subjected to chronic UV exposure (Group 2). After 24 hours of exposure to UV light, all mice showed an erythematous reaction, which disappeared within 3-5 days after irradiation. Likewise, most of the mice presented wounds and dry skin during the first weeks of exposure to UV light. The first papillomatous lesions began to appear around the 18th week of irradiation. Similar results were observed in Group 4, corresponding to animals treated with a vehicle and subsequently exposed to the UV light. It should be noted that in this case a mouse was found with inguinal axillary tumors, as well as two mice with ocular lesions. Group 3 animals showed a mild erythema after irradiation and, in general, showed a good cutaneous appearance with few wounds and few papillomatous lesions.

Likewise, as reflected in Table 3 and in Fig. 2, there was a notable increase in the number and size of tumors of mice in Groups 2 and 4, while mice treated with EADA before exposure to the source of UV showed a smaller number of tumors (papillomatous lesions and carcinomas). The average number of tumors counted for Groups 2 and 4 was 7.5 ± 3.6 and 3.0 ± 1.3 respectively and the average size of these tumors was 0.27 ± 0.11 cm and 0.21 ± 0.1 cm respectively (Table 4). However, mice treated with EADA before exposure to the UV light source showed a smaller number of tumors (papillomatous lesions and carcinomas) (1.25 ± 1.2) and of a smaller size (0.125 ± 0.07 cm).

TABLE 4

Total number of papillomatous lesions of a size greater than 0.15 mm in diameter and the size thereof present in each experimental group at the end of the experiment (25 weeks after starting irradiation with UV light) .a Group dosages 2 and Group 4 mice were sacrificed within 21 weeks of starting Experimentation for presenting a tumor larger than 0.5 cm b Very thin mouse without tumors c Mouse presented a tumor in the uncounted right ear d. Mouse that presented an uncounted ventral tumor. e Mouse that presented two axillary tumors, lymph node position not counted

Statistical analyzes show that the number of papillomatous lesions induced in mice by chronic exposure to UV light is significantly greater and, in addition, the average size of them is also larger than those observed in mice treated with EADA before being exposed to UV light. These differences have been manifested by the Mande-Whitney Ude test:

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Variable "No. of tumors": P = 0.002; Sig <0.05

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Variable "average tumor size": P = 0.005; Sig. <0.05

Significant differences have also been observed in relation to the number and size of tumors between mice treated with EADA before being exposed to UV light, compared to mice treated with the vehicle (Carbopol) and then irradiated with UV light. In the latter case, both Number as the size of the tumors are significantly larger, according to the Mann-Whitney Ude test:

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Variable “No. of tumors”: P = 0.012; Sig <0.05

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Variable "average tumor size": P = 0.002; Sig. <0.05

The result of the Pearson chi-square test shows that the number of tumors developed depends on the type of treatment to which the mice are subjected, while the average tumor size does not depend on the treatment applied:

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Variable "No. of tumors": P = 0.011; Sig. <0.05

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Variable "average size of tumors": P = 0.132; Sig. <0.05

Finally, it is verified that by applying the chi-square test of Pearson that the average size of the tumors is dependent on the number of tumors found in each treatment (P <0.0001, Sig <0.05).

The results obtained throughout this study allow us to conclude that the topical application of EADA containing the extract of Antarctica Deschampsia (300 mg / ml) on the skin of the back of SHK-1 mice has a preventive effect of skin damage caused by UV light Mice treated with EADA before exposure to UV light show, in the short term, a marked decrease in skin disorders (dryness, wounds), in relation to untreated conelextractoysometidosala luzUV. Likewise, treated mice develop, in the long term, a smaller number of papillomatous lesions and carcinomas compared to untreated animals.

Claims (11)

1.Use of an anthropological application that contains an extract of a plant belonging to the family of grasses from the Antarctic continent, or from areas with cold climates similar to those of the Antarctic continent, for the prevention of skin lesions caused by ultraviolet radiation in both humans and animals. 2. Use according to claim 1 in which the grass is selected from the Deschampsia, Ballica or Festuca family. 3. The use according to claim 1 and 2 in the tract of the Deschampsia Antarctica grass. 4.According to claims 1, 2 and 3, in which the composition has a concentration ranging from 150 mg / ml to 500 mg / ml, preferably 300 mg / ml, of the preparation prepared by dissolving said extract in distilled water and subsequently in the compatible joint. 5. The use according to all the preceding claims in which the pharmacological composition can be presented in the form of cream, gel, gel-cream, foam or any other formulation generically accepted for topical use 6. Even according to all of the preceding claims in which the pharmaceutical composition contains products selected from the group comprising: antioxidants, physical filters, chemical filters, tanning agents and humectants. 7. The use according to claim 1 to 5 in which the skin lesion is nonmelanoma skin cancer. 8. The use according to claim 7 wherein the non-melanoma cancer is a basal cell carcinoma. 9. The use according to claim 7 wherein nonmelanoma cancer is a squamous cell carcinoma. 10. The use according to all of the preceding claims wherein the pharmacological composition is applied up to six hours before exposure to ultraviolet radiation. SPANISH OFFICE OF PATENTS AND BRANDS Application no .: 200901623 SPAIN Date of submission of the application: 07.27.2009 Date of priority: REPORT ON THE STATE OF THE TECHNIQUE 51 Int. Cl.: A61K36 / 899 (01.01.2006) A61P35 / 00 (01.01.2006) RELEVANT DOCUMENTS

Category

Documents cited Claims Affected

X

UNIVERSIA.CL "University of La Frontera earns four FONDEF: Millionaire investment for applied research". Source Universidad La Frontera, 08.06.2004, page 1 [online] [retrieved on 07.12.2010] Recovered from the Internet: <URL: http://www.ufro.cl/prensa/doc/2004/June 07-13 /08June-%20Universia-%20cuatro%20fondef.pdf 1-3,5,6,10

X

 THE PLANT THAT MOVES SCIENCE. UFRO leads attractive research with "Antarctic Deschampsia". Chronicle, 08.06.2004, pages 1-4, See pages 2-3, Object of Study. [online] [retrieved on 07.12.2010] Recovered the Internet: <URL: http://www.ufro.cl/prensa/doc/2004/June 07-13/08June-%20Austral-%20La%20planta%20 that% 20moves% 20a% 20la% 20ciencia.pdf 1-3,5,6,10

X

PEREIRA, B. K. et al. "Protective effects of three extracts from Antarctic plants against ultraviolet radiation in several biological models." Journal of Photochemistry and Photobiology B: Biology. 06.05.2009. Vol. 26, No. 2, pages 117-129. doi: 10.1016 / j.jphotobiol. 2009.04.011. 1-3,5,6,10

X

WO 2009 064480 A1 (GIDEKEL, M. et al.) 05.22.2009, pages 4.5; claims 1,10-19. 1-3,5,6,10

Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application

This report has been prepared • for all claims □ for claims no:

Date of realization of the report 09.12.2010

Examiner A. Sukhwani Page 1/5

REPORT OF THE STATE OF THE TECHNIQUE Application number: 200901623 Minimum documentation searched (classification system followed by classification symbols) A61K, A61P Electronic databases consulted during the search (name of the database and, if possible, terms of search used) INVENES, EPODOC, WPI, BIOSIS, MEDLINE, X-FULL, NPL, TCM, XPTK, HCAPLUS, LIFESCI, PASCAL, SCISEARCH, NAPRALERT  WRITTEN OPINION Application number: 200901623 Date of Written Opinion: 09.12.2010 Statement

Novelty (Art. 6.1 LP 11/1986)

Claims Claims 1 -10 IF NOT

Inventive activity (Art. 8.1 LP11 / 1986)

Claims Claims 4, 7-9 1-3, 5, 6, 10 IF NOT

The application is considered to comply with the industrial application requirement. This requirement was evaluated during the formal and technical examination phase of the application (Article 31.2 Law 11/1986).  Opinion Base.- This opinion has been made on the basis of the patent application as published.  Considerations: The present invention aims at the use of a topical application pharmacological composition containing an extract of a plant belonging to the grass family from the Antarctic continent, or from areas with similar cold climates, for the prevention of skin lesions caused by ultraviolet radiation in both humans and animals (claim 1). The grass is selected from the family of Deschampsia, Ballica or Festuca (reiv. 2), the extract of the grass being Deschampsia antarctica (reiv. 3) The composition has a concentration that varies between 150 mg / ml and 500 mg / ml, preferably 300 mg / ml of the extract, prepared by dissolving said extract in distilled water and subsequently in an inert gel or compatible vehicle (reiv. 4 ) and can be presented in the form of cream, gel, cream-gel, foam or any other formulation accepted for topical use (reiv. 5). In addition, the composition may contain antioxidant products, physical filters, chemical filters, tanning agents and humectants (reiv. 6). The use of the composition in which the skin lesion is nonmelanoma skin cancer, whether basal cell carcinoma or squamous cell carcinoma (reivs. 7-9), is also subject to protection. Finally, the application of the pharmacological composition is protected until six hours before exposure to ultraviolet radiation (reiv. 10).  WRITTEN OPINION Application number: 200901623 1. Documents considered.- The documents belonging to the state of the art taken into consideration for the realization of this opinion are listed below.

Document

Publication or Identification Number publication date

D01

UNIVERSIA.CL "University of La Frontera earns four FONDEF: Millionaire investment for applied research". Source Universidad La Frontera, 08.06.2004, page 1. [online] [retrieved on 07.12.2010] Recovered from the Internet: <URL: http://www.ufro.cl/prensa/doc/2004/June 07- June 13, 2018-% 20Universia% 20cuatro% 20fondef.pdf 06.08.2004

D02

THE PLANT THAT MOVES SCIENCE. UFRO leads attractive research with "Antarctic Deschampsia". Chronicle, 08.06.2004, pages 1-4, See pages 2-3, Object of Study. [online] [retrieved 07.12.2010] Recovered Internet: <URL: http://www.ufro.cl/prensa/doc/2004/June 07-13/08June-%20Austral%20La%20planta%20que% 20mueve% 20a% 20la% 20ciencia.pdf 06.08.2004

D03

PEREIRA, B. K. et al. "Protective effects of three extracts from Antarctic plants against ultraviolet radiation in several biological models." Journal of Photochemistry and Photobiology B: Biology. .2009. Vol. 26, No. 2, pages 117-129. doi: 10.1016 / j.jphotobiol. 2009.04.011 06.05.2009

D04

WO 2009 064480 A1 (GIDEKEL, M. ET AL.) 05/22/2009

2. Statement motivated according to articles 29.6 and 29.7 of the Regulations for the execution of Law 11/1986, of March 20, on Patents on novelty and inventive activity; quotes and explanations in support of this statement  NOVELTY Documents cited D01 and D02 refer to research projects on the properties of the grass of the Antarctic, Deschampsia antarctica, and their properties that make it highly tolerant of cold and that will allow to create photoprotective lotions and, later, effective products in diseases of the skin and in dermocosmetics. However, these two documents cited do not disclose a pharmacological composition containing the extract of this plant. D03 refers to the protective effects of three plant extracts of the Antarctica against ultraviolet radiation in several biological models, however it does not disclose that it serves to prevent skin lesions. On the other hand, document D04 refers to the neoplastic activity of the extract of the species Deschampsia antarctica against cancer of color, liver, etc. but does not disclose the topical use of this extract for the prevention of skin lesions. Therefore, it can be concluded that claims 1-10 are new in accordance with Article 6 LP 11/86.  INVENTIVE ACTIVITY The purpose of using a topical application pharmacological composition containing an extract of a grass plant from the Antarctic continent for the prevention of skin lesions caused by ultraviolet radiation in humans and animals, is evident to those skilled in the art in view of documents D01, D02 and D03. Indeed,

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D01 reports that the only grass plant that exists in Antarctica, Deschampsia antarctica has properties that make it highly tolerant of cold and radiation. This research will allow to create photoprotective lotions and henceforth other effective products in skin diseases (see first paragraph of “Innovation and Transfer”). The person skilled in the art, in view of this disclosure, could prepare topical application pharmacological compositions to prevent skin lesions as the application under study (claims 1-3, 5, 6, 10) without any inventive effort.

Similarly for the documents cited D02 and D03.

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D02 refers to a publication that discloses the genetic qualities of the Deschampsia antarctica plant that make it tolerant of ultraviolet rays, with the aim of creating a photoprotective lotion for dermatological use (pages 2 and 3, paragraph "Object of Study").

State of the Art Report Page 4/5  WRITTEN OPINION Application number: 200901623

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D03 discloses the protective effects of three Antarctic plant extracts against ultraviolet radiation in several biological models. Among the three species is Deschampsia antarctica.

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D04 is a document that refers to the antineoplastic extract obtained from Deschampsia antarctica (pages 4 and 5) and that can be used orally to prevent the proliferation of cancer cells (claims 1, 10-19). The skilled artisan in view of these disclosures of cancer cell proliferation prevention could do topical use tests, in particular, to prevent skin lesions.

The intervals of quantities, the form of presentation in cream, gel, foam, etc. and of incorporating antioxidants, filters, broaching agents and application before exposure are evident to the expert in this sector of the art. Therefore, in view of documents D01-D04, it can be concluded that claims 1-3, 5, 6 and 10 lack inventive activity in accordance with Article 8 LP 11/86. State of the Art Report Page 5/5