(19)
(11)EP 3 663 309 A1

(12)EUROPEAN PATENT APPLICATION
published in accordance with Art. 153(4) EPC

(43)Date of publication:
10.06.2020 Bulletin 2020/24

(21)Application number: 18840290.3

(22)Date of filing:  01.06.2018
(51)International Patent Classification (IPC): 
C07J 71/00(2006.01)
A61K 36/886(2006.01)
A61P 17/00(2006.01)
A61K 31/7048(2006.01)
A61P 17/06(2006.01)
(86)International application number:
PCT/BR2018/050181
(87)International publication number:
WO 2019/023769 (07.02.2019 Gazette  2019/06)
(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
Designated Extension States:
BA ME
Designated Validation States:
KH MA MD TN

(30)Priority: 01.08.2017 BR 102017016550

(71)Applicants:
  • Gomes, Lisis Rojo
    04149-100 São Paulo - SP (BR)
  • Pianowski, Luiz Francisco
    12917-025 Bragança Paulista - SP (BR)

(72)Inventors:
  • Gomes, Lisis Rojo
    04149-100 São Paulo - SP (BR)
  • Pianowski, Luiz Francisco
    12917-025 Bragança Paulista - SP (BR)

(74)Representative: KATZAROV S.A. 
European Patent Attorneys 12, Avenue des Morgines
1213 Petit-Lancy
1213 Petit-Lancy (CH)

  


(54)USE OF STEROIDAL GLYCOSIDES, PHARMACEUTICAL FORMULATIONS, USE OF FURCRAEA FOETIDA PLANT EXTRACTS, PROCESS FOR PRODUCING FURCRAEA FOETIDA PLANT EXTRACTS AND METHOD FOR TREATING SKIN DISORDERS


(57) The present invention relates, in its broadest aspects, to steroidal glycosides useful in the treatment of skin disorders. Particularly, the invention relates to the use of certain steroidal glucosides, per se, or in the form aglycona, derivatives of spirostanol, of its precursor furastanol, or mixtures thereof, used in the treatment of skin disorders, for instance, psoriasis. The invention further relates to formulations containing steroidal glycosides, the process of obtaining extract from the Furcraea foetida plant, and a method of treating skin disorders.


Description


[0001] The present invention relates, in its broadest aspects, to steroidal glycosides useful in the treatment of skin disorders.

[0002] Particularly, the invention relates to the use of certain steroidal glucosides, per se, or in the form of aglycona, derivatives of spirostanol, of its precursor furastanol, or mixtures thereof, used in the treatment of skin disorders, for instance, psoriasis. The invention further relates to formulations containing steroidal glycosides, the process of obtaining extract from the Furcraea foetida plant, and a method of treating skin disorders.

[0003] As per mentioned herein, the following terms have the following meanings:
  • Glycoside: molecule in which one or more structural groups derived from sugar are linked to another functional group, through a glucosidic bond. Such structural groups derived from sugar are, in general, one or more amongst glucose, rhamnose, galactose, fucose, mannose, fructose, ribose, xylose, arabinose, and glucoronide. The glycosides of the present invention are, more particularly, without excluding any others, glucose, rhamnose and galactose.
  • Aglycona: non-sugar component of a steroidal glycoside.
  • Skin disorders: includes diseases and any abnormal dermatological condition, either by endogenous or exogenous causes.

PRIOR ART



[0004] Plant extracts are complex mixtures, which contain a variety of molecules, many of which causing effects to the animal and human organisms. Said mixtures often contain molecules that produce opposite effects - for instance, it is known that the latex of some plants contains both inflammatory and cancerous molecules, as well as molecules having anti-inflammatory and anti-cancer capabilities.

[0005] Regarding studies of the composition of mentioned plant extracts, they are typically subjected to the steps of separating their components by affinities to certain solvents, and different fractions are individually tested concerning specific effects. Such separation possibly progresses in a certain way in which it is possible to identify one or more active molecules, which alone or in conjunction provide beneficial effects.

[0006] The procedure described above is classical and allows both the detection and the obtention of natural actives important to human or animal health. Such actives can also be synthesized and modified.

[0007] In the following description, psoriasis is mentioned simply to ease the explanation, therefore, the invention should not be limited only to the abovementioned skin disorder.

[0008] The present invention relates, in a first aspect, to the use of steroidal glucosides of the Z-A type, in the preparation of formulations useful to treatment of skin disorders, in particular, to psoriasis, wherein A is a spiroestanol type structure of formula I,



or a furanol type structure of formula II

wherein R is H, H or O;
and Z represents H or one or more saccharide groups, particularly having 1 to 12 rings, more particularly having 6 rings. Such rings are, for instance, one or more amongst glucose, rhamnose, galactose, fucose, mannose, fructose, ribose, xylose, arabinose, glucoronide. In particular such rings are one or more amongst glucose, rhamnose and galactose.

[0009] Within a particular embodiment, steroidal glycosides used in the present invention are one or more amongst:
  • (24S,25S)-24-[(-Beta-D-glucopyranosyl)oxy]-5 alpha-spirostan-3 Beta-yl-Beta-D-glucopyranosyl-(1→3)-O-Beta-D-glucopyranosyl-(1→2)-O-[O-alpha-L-rhamnopyranosyl-(1→4 Beta D-glucopyranosyl-(1→3)]-O-Beta-D-glucopyranosyl-(1→4)-Beta-D-galactopyranoside;
  • (23S,25R)-6 alpha-[(Beta-D-glucopyranosyl)oxy]-23-hydroxy-5 alpha-spirostan-3 beta-D-fucoidan;
  • (25R)-26-[(beta-D-glucopyranosyl))oxy] -6 alpha-hydroxy-22 alpha-methoxy-5 alpha-furoan-3 beta-yl-O-beta-D-glucopyranosyl-(1 → 3)-O-Beta-D-glucopyranosyl-(1→2)-O-[O-alpha-1-rhamnopyranosyl-(1 → 4)-beta-D-glucopyranosyl-(1→3)]-O-beta-D-glucopyranosyl-(1 → 4)-beta-D-galactopyranoside;
  • (25R)-5 alpha-spirostan-3 beta-Yl-O-Beta-D-glucopyranosyl-(1 → 3)-O-beta-D-glucopyranosyl-(1 → 2)-O-[O-alpha-1-rhamnopyranosyl-(1 → 4)-beta-D-Glucopyranosyl-(1 → 3)]-O-beta-D-glucopyranosyl-(1 → 4)-beta-D-galactopyranoside;
  • (25R)-6 alpha-hydroxy-5 alpha-spirostan-3 beta-yl O-Beta-D-glucopyranosyl-(1 → 3)-O-beta-D-glucopyranosyl-(1 → 2)-O-[O-alpha-1-rhamnopyranosyl-(1 → 4)-beta-D-Glucopyranosyl-(1 → 3)]-O-beta-D-glucopyranosyl-(1 → 4)-beta-D-galactopyranoside;
  • (25R) -3 beta-[(O-Beta-D-glucopyranosyl-(1 → 3)-O-beta-D-glucopyranosyl-(1 → 2)-O-[O-alpha-1-rhamnopyranosyl-(1 → 4)-beta-D-Glucopyranosyl-(1 → 3)]-O-beta-D-glucopyranosyl-(1 → 4)-beta-D-galactopyranosyl) oxy]-5 alpha-spirostan-12-one (furcreastatin);
  • (23S,25R)-3 beta, 23-dihydroxy-5 alpha-spirostan-6 alpha-yl-Beta-D-glucopyranoside;
  • (25R) -5 alpha-spirostane-3 beta, 6α-di-I-bis-beta-beta-D-glucopyranoside;
  • (23S,25R)-23-hydroxy-5 alpha-spirostane-3 beta, 6α-di-yl bis-Beta-D-glucopyranoside;
  • (25R)-26-[(beta-D-glucopyranosyl)oxy]-22 alpha-methoxy-5 alpha-furoan-3 beta-yl-O-beta-D-glucopyranosyl-(1 → 3)-O-beta-D-glucopyranosyl-(1 → 2)-O-[O-alpha-1-rhamnopyranosyl-(1 → 4)-beta-D-glucopyranosyl-(1 → 3)]-O-beta-D-Glucopyranosyl-(1 → 4)-beta-D-galactopyranoside;
  • (25R) -3 beta-[(O-beta-D-glucopyranosyl-(1 →3)-O-beta-D-glucopyranosyl-(1 → 2)-O-[O-Alpha-1-rhamnopyranosyl-(1 → 4)-beta-D-glucopyranosyl-(1 → 3)]-O-beta-D-glucopyranosyl-(1 → 4)-beta-D-galactopyranosyl)oxy]-26 a-[(beta-D-glucopyranosyl)oxy]-22-methoxy-5 a-furoan-12-one;
  • (25R)-22 alpha-methoxy-5 alpha-furoan-3 beta, 6α, 26-triyl tris-beta-D-glucopyra noside.


[0010] Particularly, A has the spatial structure of formula III



[0011] Particularly, Z is a hexasaccharide, as per formula IV:





[0012] Within a particular embodiment, the steroidal glycoside Z-A used in the present invention is (25R)-6 alpha-hydroxy-5 alpha-spirostan-3 beta-yl o-beta-D-glucopyranosyl-(1 → 3)-o-Beta-D-glucopyranosyl-(1 → 2)-o-[O-alpha-1-rhamnopyranosyl-(1 → 4)-beta-D-glucopyranosyl-(1 → 3)]-o-beta-D-glucopyranosyl-(1 → 4)-beta-D-galactopyranoside.

[0013] In general, the skin disorders treatable with the steroidal glycosides used in the present invention are, without excluding any others, one or more amongst acne, rosacea, psoriasis, skin vesicles, sun burns, physical or chemical burns, dermatitis, eczema, skin rash, allergic reactions, fungal, bacterial and viral infections, pruritis, cellulite, urticaria, chapped lips, tattoos, waxed areas, diabetic ulcer, radiation dermatitis, scleroderma, erisiper, ictiosis decubities, cracked feet and hands.

[0014] A further aspect in the present invention relates to pharmaceutical formulations comprising one or more of the aforementioned steroidal glucosides, useful in the treatment of skin disorders, and at least one or more excipient, vehicle or carrier.

[0015] Another aspect in the present invention relates to the use of extracts from the Furcraea foetida plant, which contain one or more of the abovementioned steroidal glucosides used in the preparation of formulations useful in the treatment of skin disorders, particularly, psoriasis.

[0016] A further aspect of the present invention relates to the process for obtaining extracts from the Furcraea foetida plant, which contain one or more of the abovementioned steroidal glucosides used in the preparation of formulations useful in the treatment of skin disorders, particularly, psoriasis.

[0017] A process for obtaining extracts mentioned in the previous paragraph, comprises at least one contacting step - particularly maceration - of any parts of the Furcraea foetida plant (specially the leaves) with one or more carrier solvents of the steroidal glucoside(s) or saponins contained in the plant. Without excluding any other alternative, one or more of the following alcohols are examples of solvents suitable for the aforementioned extraction: ethanol, methanol, propanol, butanol, propanediol and propylene glycol, alone or in hydroalcoholic mixture, having a single-step extraction or consecutive steps. The use of suitable solvents in the present invention considers specific toxicities. The parts of the plant referred to herein are, preferably, previously milled, milled, powdered, cut, crushed or subjected to any operation capable of breaking up such parts prior to the contact with solvent. After suitable time in contact between the parts of the plant and the solvent, one or more suitable operations for solid/liquid separation are provided, for instance, filtration, decantation, centrifugation, or any other known process in the prior art. The obtained liquid from this solid/liquid separation may further, optionally be separated into distinct fractions through chromatography or any equivalent process known, by selecting the fractions containing higher levels of specific steroidal glycosides.

[0018] It is noted that the steroidal glycosides used in the present invention, as it is well-known to a person skilled in the art, can be synthetic, for instance, obtained by the synthesis of Koenigs-Knorr (W. Koenigs and E. Knorr; Chem. Ber., 1901, 34; 952) or modifications thereof (C. Meystre and K. Miescher Helv. Chim. Acta; 1944, 27, 231-236; R. B. Courow e S. Bernstein; Org. Chem. 1971, 36, 863-870; J. J. Schneider; Carbohyd. Res.; 1970, 12; 369-389; G. Wulff and G. Roehle; Angew. Chemie. 1974; 86, 173-187; N. Weber; Chem. Phys. Lipids; 1977; 18, 145-146), or by the orthoester method (N. I. Ovarova; Carbohyd. Res. 1973; 27; 79-87) by treating hydroxy-spirocetanoid 3-beta-aglycones with a brominated C -1 orthoester or with a mono-or disaccharide 1,2-orthoester acetate in the presence of silver oxide, silver carbonate or other suitable catalysts.

[0019] A further aspect of the present invention relates to a method of treating skin disorders, characterized by the administration of a pharmaceutically acceptable amount, of one or more of the abovementioned steroidal glucosides, to a subject in need of treatment.

[0020] When the treatment of skin disorders addressed by the present invention is applied through a topical via, it is characterized by placing a pharmaceutically acceptable amount, of one or more steroidal glucosides aforementioned, in contact with the skin.

[0021] The steroidal glycosides of the present invention may be natural or synthetic.

[0022] The use of the steroidal glycosides of the present invention is made through the use of formulations suitable for the intended purpose, as well-known to those persons skilled in the art. In the particular case of a topical application, such formulations may contain ingredients that are both active ingredients (in addition to the steroidal glycosides referred to herein) and pharmaceutically acceptable excipients.

[0023] The term "active principle" means a substance biologically active to the animal or human body.

[0024] Non-limiting examples of active principles that may be contained in the formulation used in the invention, besides steroidal glucosides, are one or more amongst agents with antibiotic, moisturizer, emollient, sunscreen, healing, anti-wrinkle, anti-itching, anti-inflammatory, and anti-inflammatory effects.

[0025] The term "pharmaceutically acceptable excipients" refers to substances used in pharmaceutical formulations such as diluents, carriers or additives, having no medicative activity. The following publications in the prior art are representative of sources known by those people skilled in the art concerning pharmaceutical excipients: "Remington: The Science and Practice of Pharmacy" (2000), 20th edition or later editions, Lippincott, Williams & Wilkins Publishing Company; "Pharmaceutical Dosage Forms and Drug Delivery Systems" (1999), H.C. Ansel et al., 7h edition, Lippincott, Williams & Wilkins Publishing Company; "Handbook of Pharmaceutical Excipients" (2000), A. H. Kibbe et al, 3rd edition, American Pharmaceutical Association Publishing Company.

[0026] There are no specific restrictions regarding the way the formulations which contain steroidal glycosides are administrated, as per the present invention, for instance, orally, topical, intradermic, amongst others.

[0027] Non-limiting examples of solid oral administration forms suitable to the present invention are as follows: pills, tablets, capsules, granules, pellets or powder. The powders may be lyophilized. For topical administration, the following products may be used: lotions, ointment, unguents, solutions, dispersions, emulsions, oils, etc. Other forms of administrations suitable to the present invention are liposomes and nanoparticles, or any other form well-known to a person skilled in the art.

[0028] The administrations forms suitable to the present invention may further present immediate, prolonged or controlled liberation.

[0029] Further below are examples that disclose particular embodiments related to the present invention, without, for this reason, limiting the scope, in any way, of the protection presented in the attached set of claims.

EXAMPLE 1 - Process for obtaining the extract



[0030] 30 parts in weight of ethanol and 70 parts in weight of Furcraea foetida leaves pulp, previously crushed, are blended in and left in contact together for a certain amount of time, for instance, until 48 hours. It is followed by filtration.

EXAMPLE 2 - Formulation and treatment



[0031] The liquid of example 1 is formulated as a lotion, which is applied, periodically upon skin areas affected by psoriasis. After a few applications, it can be observed that the disease regression, both visually and concerning the pruritus, occurs in a fast and effective way.

[0032] A person skilled in the art will be able to, from the information and examples provided herein, perform the invention in equivalent forms, not expressly disclosed, however, with the same, or substantially the same function, and the same, or substantially the same results, even though they are under the protective scope of the attached set of claims.


Claims

1. Use of steroidal glucosides of the Z-A type, characterized for being used in the preparation of formulations useful in the treatment of skin disorders, wherein A is an espiroestanol structure type, of formula I.

or a furanol type structure of formula II

wherein R is H, H or O;
and Z represents H or one or more saccharide groups, particularly having 1 to 12 rings.
 
2. Use, according to claim 1, characterized by the fact that A has the spacial structure of formula III


 
3. Use, according to claim 1, characterized by the fact that Z represents one or more saccharide groups, having 6 rings.
 
4. Use, according to claim 1, characterized by the fact that said one or more saccharide groups are chosen amongst glucose, rhamnose, galactose, fucose, mannose, fructose, ribose, xylose, arabinose, and glucoronide.
 
5. Use, according to claim 1, characterized by the fact that said one or more saccharide groups are chosen amongst glucose, rhamnose, and galactose.
 
6. Use, according to claim 1, characterized by the fact that said steroidal glycosides are one or more amongst:

• (24S,25S)-24-[(-beta-D-glucopyranosyl)oxy]-5 alpha-furoan-3 beta -yl-beta-D-glucopyranosyl-(1→3)-O-beta-D-glucopyranosyl-(1→2)-O-[O-alpha-L-rhamnopyranosyl-(1→4)-beta-D-glucopyranosyl-(1→3)]-O-beta-D-glucopyranosyl-(1→4)-beta-D-galactopyranoside;

• (23S,25R)-6 alpha-[(Beta-D-glucopyranosyl)oxy]-23-hydroxy-5 alpha-spirostan -3 beta-D-fucoidan;

• (25R)-26-[(beta-D-glucopyranosyl))oxy]-6 alpha-hydroxy-22 alpha-methoxy-5 alpha-furoan-3 beta-yl-O-beta-D-glucopyranosyl-(1 → 3)-O-Beta-D-glucopyranosyl-(1 → 2)-O-[O-alpha-1-rhamnopyranosyl-(1 → 4)-beta-D-glucopyranosyl-(1 → 3)]-O-beta-D-glucopyranosyl-(1 → 4)-beta-D-galactopyranoside;

• (25R)-5 alpha-spirostan-3 beta-Yl-O-Beta-D-glucopyranosyl-(1 → 3)-O-beta-D-glucopyranosyl-(1 → 2)-O-[O-alpha-1-rhamnopyranosyl-(1 → 4)-beta-D-Glucopyranosyl-(1 → 3)]-O-beta-D-glucopyranosyl-(1 → 4)-beta-D-galactopyra noside;

• (25R)-6 alpha-hydroxy-5 alpha-spirostan-3 beta-yl O-Beta-D-glucopyranosyl-(1 → 3)-O-beta-D-glucopyranosyl-(1 → 2)-O-[O-alpha-1-rhamnopyranosyl-(1 → 4)-beta-D-Glucopyranosyl-(1 → 3)]-O-beta-D-glucopyranosyl-(1 → 4)-beta-D-galactopyranoside;

• (25R)-3 beta-[(O- beta-D-glucopyranosyl-(1→3)-O-beta -D-glucopyranosyl-(1→2)-O-[O-alpha-L-rhamnopyranosyl-(1→4)-beta-D-glucopyranosyl-(1→3)]-O-beta-D-glucopyranosyl-(1→4)-beta-D-galactopyranoside)oxy]-5 alpha-spirostan-12-one (furcreastatin); (23S,25R)-3 beta, 23-dihydroxy-5 alpha-spirostan-6 alpha-yl-Beta-D-glucopyranoside;

• (25R)-5 alpha-spirostane-3 beta, 6α-di-l-bis-beta-beta-D-glucopyranoside;

• (23S,25R)-23-hydroxy-5 alpha-spirostane-3 beta, 6α-di-yl bis-Beta-D-glucopyranoside;

• (25R)-26-[(beta-D-glucopyranosyl)oxy]-22 alpha-methoxy-5 alpha-furoan-3 beta-yl-O-beta-D-glucopyranosyl-(1 → 3)-O-beta-D-glucopyranosyl-(1 → 2)-O-[O-alpha-1-rhamnopyranosyl-(1 → 4)-beta-D-glucopyranosyl-(1 → 3)]-O-beta-D-Glucopyranosyl-(1 → 4)-beta-D-galactopyranoside;

• (25R)-3 beta-[(O-beta-D-glucopyranosyl-(1 → 3)-O-beta-D-glucopyranosyl-(1 → 2)-O-[O-Alpha-1-rhamnopyranosyl-(1 → 4)-beta-D-glucopyranosyl-(1 → 3)]-O-beta-D-glucopyranosyl-(1 → 4)-beta-D-galactopyranosyl)oxy]-26 a-[(beta-D-glucopyranosyl)oxy]-22-methoxy-5 a-furoan-12-one;

• (25R)-22 alpha-methoxy-5 alpha-furoan-3 beta, 6α, 26-triyl tris-beta-D-glucopyranoside.


 
7. Use, according to claim 1, characterized by the fact that Z is a hexasaccharide, as per formula IV:


 
8. Use, according to claim 1, characterized by the fact that one of abovementioned steroidal glycosides is (25R)-6 Alpha-hydroxy-5 Alpha-espirostan-3 beta-yl O-beta-D-glucopyranosyl-(1→3)-O-beta-D-glucopyranosyl-(1→2)-O-[O-Alpha-L-rhamnopyranosyl-(1→4)-beta-D-glucopyranosyl-(1→3)]-O-beta-D-glucopyranosyl-(1→4)-beta-D-galactopyranosyl.
 
9. Use, according to claim 1, characterized by the fact that said the skin disorders are one or more amongst acne, rosacea, psoriasis, skin vesicles, sun burns, physical or chemical burns, dermatitis, eczema, skin rash, allergic reactions, fungal, bacterial and viral infections, pruritis, cellulite, urticaria, chapped lips, tattoos, waxed areas, diabetic ulcer, radiation dermatitis, scleroderma, erisiper, ictiosis decubibies, cracked feet and hands.
 
10. Pharmaceutical formulations, characterized for comprising one or more of the steroidal glucosides, of any of previous claims 1 to 8, and at least one or more excipient, vehicle or carrier.
 
11. Use of extracts from the Furcraea foetida plant, which contain one or more of the steroidal glucosides of claim 1, characterized for being used in the preparation of formulations useful in the treatment of skin disorders.
 
12. Use, according to claim 11, characterized by the fact that said the skin disorders are one or more amongst acne, rosacea, psoriasis, skin vesicles, sun burns, physical or chemical burns, dermatitis, eczema, skin rash, allergic reactions, fungal, bacterial and viral infections, pruritis, cellulite, urticaria, chapped lips, tattoos, waxed areas, diabetic ulcer, radiation dermatitis, scleroderma, erisiper, ictiosis decubibies, cracked feet and hands.
 
13. Process for obtaining extracts from the Furcraea foetida plant, which contain one or more steroidal glucosides of claim 1, characterized for comprising the steps of:

- providing the contact of parts of the plant with one or more carrier solvents of the steroidal glucosides or saponins contained in the plant, as per disclosed in claim 1.

- maintain the contact for a suitable amount of time, particularly until 48 hours;

- providing the separation solid/liquid;

- optionally providing the separation of liquid fractions.


 
14. Process, according to claim 13, characterized by the fact that said one or more solvents are chosen amongst ethanol, methanol, propanol, butanol, propanediol, propylene glycol, and hydroalcoholic mixtures thereof.
 
15. Method of treating skin disorders, characterized by the administration of a pharmaceutically acceptable amount, of one or more of the abovementioned steroidal glucosides, of claim 1, to a subject in need of treatment.
 





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Cited references

REFERENCES CITED IN THE DESCRIPTION



This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Non-patent literature cited in the description