WO2015107554A1

WO2015107554A1 - A composition for use in treatment of dermatological diseases, and relative pharmaceutical preparations

Info

Publication number: WO2015107554A1
Application number: PCT/IT2014/000065
Authority: WO
Inventors: Jacopo LOTTI; Emiliano MISURACA; Victoria BARYGINA
Original assignee: MINUTILLO, Claudia
Priority date: 2014-01-14
Filing date: 2014-03-06
Publication date: 2015-07-23

Abstract

A composition for the topical treatment of dermatological diseases, and the relative pharmaceutical preparations, comprising an anti-inflammatory substance (4), an antioxidant substance (5) and an active substance (6), at least one of said substances, preferably said active substance (6), being suitable to be conveyed through a biodegradable nanovector (1).

Description

"A composition for use in treatment of dermatological diseases_/ and relative pharmaceutical preparations"

DESCRIPTION

Technical field

The present invention relates to a composition for the treatment of dermatological diseases.

More precisely, the present invention relates to a composition for the topical treatment of dermatological diseases.

The present invention is specifically aimed at the treatment of diseases such as vitiligo and psoriasis.

The present invention also concerns pharmaceutical preparations, nutritional supplements, cosmetics, hair products for internal and external use, veterinary nutritional supplements and veterinary cosmetics comprising said composition for the treatment of dermatological diseases.

Known Trior Art

Currently, the treatment of dermatological diseases, such as psoriasis and vitiligo, is carried out through immunosuppressive drugs and strong neurogenic antiinflammatory substances administered by general and/or local means with constant and often severe side effects in the medium and long term.

However, the aforesaid treatments cure the symptom and not even the underlying causes of the generation of such a symptom. In particular, the aforesaid treatments are neither able to remove the inflammatory origin of the disease nor to prevent its degeneration. The solutions proposed so far, therefore, do not satisfactorily respond to the problem of healing and strengthening the skin cells, by acting on the origins of the disease.

Another problem that is still partially unsolved is the treatment effectiveness over time. Among the currently existing treatments, in fact, the most common are limited to the superficial skin layers, thus causing the disease recurrence after a certain period of time. A number of studies illustrating the treatment of vitiligo and psoriasis are known. Particularly_/ in a very recent publication by Lotti T, Hercogova J, Schwartz RA, Tsampau D, Korobko I, Pietrzak A, itrevska NT, Valle Y, Buggiani G; ''Treatments of vitiligo: whafs new at the horizon"; Dermatol Ther. 25 Suppl l:S32-40; Nov-Dec, 2012 the most classic and innovative therapeutic approaches to vitiligo are described, and another publication by Samarasekera E, Sawyer L, Parnham J, Smith CH; "Assessment and management of psoriasis: summary of NICE guidance"; Guideline Development Group; BMJ 345:e6712; Oct 24, 2012 represents the "handbook" for dealing with psoriasis,

In particular, the scientific literature reports many evidences supporting the use of certain specific natural substances in the different diseases, such as Khellin (Amni Visnaga) as regards vitiligo, Fumaria Officinalis for psoriasis and Oenothera Biennis for atopic dermatitis. The scientific publications indicate that excellent therapeutic performances are achieved, significant adverse effects being absent, as described in the publication "Natural Antioxidants in General Medicine and in Dermatology";

Editors: Lotti T, Turini D, Hercogova J; Associated Editors: Barygina V, Tognetti L, Valle Y; Publisher: WHA-World Health Academy; ASIN:B00B WE3ZU (Amazort e- book); Feb 28, 2013.

Moreover, in the latter publication, a collection of articles reflecting the highest world scientific level with a 360° view of the antioxidants (chemical, biological and clinical aspects) is present, outlining the redox balance in both physiological and pathological conditions.

In a further publication by Lotti T, Bianchi B, Panconesi E; "Neuropeptides and skin disorders. The new frontiers of neuro-endocrine-cutaneous immunology"; Int J Dermatol 38(9):673-5; 1999 the state of the art concerning the study of the impact of the psycho-neuro-endocrine-immune system on the main skin diseases is summarized. In particular, it is highlighted that uptaking a substance able to reduce until nullifying the neurogenic inflammation both at the systemic and at the cutaneous-mucosal level is essential. This substance has been identified in the Capsaicin, a vanilloid mainly extracted from hot pepper, which is able to degranulate the pro-inflammatory neuropeptides contained in A-delta and C sensory terminations.

The down-regulation effect of the neurogenic inflammation is essential, but not electively sufficient, in the "winning therapy" of chronic autoimmune diseases that always hesitate in an imbalance of the cellular redox system; therefore, the need to identify a solution to this problem still exists.

Objects and Brief Description of the Invention

The present invention, starting from the knowledge of the drawbacks and deficiencies of the prior art, intends to overcome them.

In particular, the present invention aims to:

- remove the inflammatory origin of skin diseases,

- prevent the cellular degeneration, and

- achieve a recovery durable over time and free from relapses.

Therefore, one object of the invention is to provide a composition for the treatment of dermatological diseases satisfactorily responding to the problem of healing and strengthening the skin cells, by acting on the origins of the disease, and that is effective over time.

More precisely, the present invention provides a composition for the treatment of dermatological pathologies that, by combining three substances with synergistic properties, allows to cure the causes and not only the symptoms of dermatological diseases such as vitiligo and psoriasis.

Moreover, more precisely, the present invention provides a composition for the treatment of dermatological diseases that, by conveying at least one of the aforesaid substances through a biodegradable nanovector, allows to solve in a definitive way (or in any case in a very effective way) dermatological diseases such as vitiligo and psoriasis.

Moreover, more precisely, the present invention provides a composition for the treatment of dermatological diseases that, starting from the down-regulation of the neurogenic inflammation and combining it with the balance of the cellular redox system, results in the "winning therapy" also for chronic autoimmune diseases, Another object of the present invention, which is obtained in parallel, is to provide a pharmaceutical preparation comprising a composition for the treatment of dermatological diseases.

A not least object of the present invention is to provide a composition, and the relative pharmaceutical preparation, which is economical and easy to be produced. In view of these objects, the present invention provides a composition and the relative pharmaceutical preparation having the features of the appended claims 1 and 15, respectively, to which reference is made for expository brevity's sake.

It is, therefore, a first subject of the present invention, possibly independent and autonomously usable with respect to other aspects of the invention, a composition for use in the treatment of dermatological diseases, specifically vitiligo and psoriasis. It is, therefore, another subject of the present invention, possibly independent and autonomously usable with respect to other aspects of the invention, a pharmaceutical preparation comprising a composition for the treatment of dermatological diseases. Advantageously, the composition for the treatment of dermatological diseases and the relative pharmaceutical preparation according to the present invention are:

- effective over time,

- safe (i.e. free from undesirable side effects) and

- economical.

Furthermore, the composition for the treatment of dermatological diseases and the relative pharmaceutical preparation according to the present invention show the advantage of optimizing the benefit/ risk ratio thanks to the use of minimal amounts of natural antioxidants suitably conveyed both at systemic and cutaneous-mucosal level through nano-size vectors. This combination of specific antioxidant molecules with synergistic effect and vectors able to selectively reach the therapeutic goal makes the composition for the treatment of dermatological diseases and the relative pharmaceutical preparation according to the present invention highly innovative and dedudbly effective and free from side effects.

Further advantageous detailed technical features of the composition for the treatment of dermatological diseases and of the relative preparation according to the present invention are described in the corresponding dependent claims.

The aforesaid claims, hereinafter defined, are considered an integral part of the present description.

Dencriprion of the Fig ure

The present invention, together with its objects and advantages, will become more apparent from the following detailed description, relevant to preferred embodiments of the composition for the treatment of dermatological diseases and of the relative pharmaceutical preparation herein exclusively claimed, given by way of indicative and illustrative, but non-limiting example with reference to the appended Figure 1, also given only by way of example, in which a biodegradable bilamellar non-ionic nanovector (niosome) according to the invention is schematically represented.

This image represents different aspects and embodiments of the present invention. Detailed Description of the Invention

While the invention is susceptible of various modifications and alternative implementations, some embodiments thereof will be described in detail hereinbelow, particularly through some illustrative examples.

It should be understood, however, that there is no intention to limit the present invention to the described specific embodiments, but, on the contrary, the invention intends to cover all the modifications, alternative implementations and equivalents that fall within the scope of the invention as defined in the appended claims.

In the following description, therefore, the use of "e.g.", "etc." and "or" denotes nonexclusive alternatives without any limitation, unless otherwise indicated; the use of "also" means "among which, but not limited to" unless otherwise indicated; the use of "includes/comprises" means "includes/comprises, but not limited to" unless otherwise indicated.

Furthermore, in the following description, the term "pharmaceutical preparation" means pharmaceutical preparations comprising the composition for use in the treatment of dermatological diseases according to the present invention and also nutritional supplements, cosmetics, hair products for internal and external use, veterinary nutritional supplements and veterinary cosmetics comprising said composition according to the present composition and also categories of preparations similar and equivalent.

As mentioned above, the present invention is addressed to the treatment of a plurality of dermatological diseases, but is mainly directed to the treatment of vitiligo and psoriasis; said diseases are peculiar for being affected by a complex autoimmune pathogenesis, having a particular significant impact on the psycho- neuro-endocrine-immune compartment. In other words, the main cause of dissatisfaction in patients with vitiligo and psoriasis currently treated with the most common therapies is not to undergo an integrated therapeutic approach of the psycho-neuro-endocrine-immune kind.

Conversely, the composition for the treatment of dermatological diseases and the relative pharmaceutical preparation according to the present invention are based on the constant neutralization of the psycho-neuro-endocrine-immune alterations involved in the onset / self-maintenance / amplification of the signs of both psoriasis and vitiligo.

The present invention is based on the finding that a dermatological disease must provide the cellular healing, thanks to the cure of their miao-neuro-inflammation, as well as the cellular strengthening, thanks to the improvement of their resistance to oxidation, as well as finally the healing treatment, thanks to the action of specific active substance.

As shown in the prior art, the antioxidant par excellence, namely esveratrol, is therefore suitably associated to the vanilloid, specifically to Capsaicin, in the composition according to the present invention. The composition according to the present invention further comprises a third agent specifically conveyed by a biodegradable nanovector having elective immunomodulating effects for the disease in questioa The electively effective third agent will vary in the composition according to the present invention depending on the disease to be treated, said third agent being anyway selected from Khellin (Amni Visnaga) as regards vitiligo, Fumaria Officinalis for psoriasis and Oenothera Biennis for atopic dermatitis.

In conclusion, all the neuro-endocrine-immune spectrum of the disease to be healed through the composition and the relative pharmaceutical preparation according to the present invention is therapeutically faced in a global and at the same time highly selective way.

A composition suitable for achieving the above-mentioned actions comprises:

a) an anti-inflammatory substance,

b) an antioxidant substance, and

c) an active substance,

at least one of said substances, preferably said active substance, being able to be conveyed through a biodegradable nanovector.

With reference to Figure 1 it can be observed that, according to a first embodiment of the invention, said biodegradable nanovector 1 is a biodegradable bilamellar non- ionic nanovector, or niosome, and comprises:

a biodegradable bilamellar non-ionic layer 2, and

an aqueous internal portion 3.

In said aqueous internal portion 3 the molecules of the above-mentioned substances are present, at least one of said substances being conveyed by said biodegradable nanovector 1, and specifically:

a) a neurogenic anti-inflammatory substance 4;

b) an antioxidant substance 5; and

c) an active substance 6.

According to a second embodiment of the invention (not shown), said biodegradable nanovector is a manipulated nanovector.

Said neurogenic anti-inflammatory substance 4 is selected from the group comprising NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) of vegetable origin. Preferably, said neurogenic anti-inflammatory substance 4 is selected from the group comprising vanilloids.

More preferably, said neurogenic anti-inflammatory substance 4 is Capsaicin.

Said antioxidant substance 5 is selected from the group comprising Polyphenols of vegetable origin.

Preferably, said antioxidant substance 5 is Resveratrol. Said active substance 6 is selected from the group comprising the Prostaglandin D2 inhibitors and/or enhancers of the Prostaglandin E2 effects.

Preferably, said active substance 6 is Genistein.

In particular, when the composition according to the present invention is for use in treatment of psoriasis in preparations for internal and external use, said active substance 6 is selected from the group comprising the immunomodulators, preferably is Astragalus Membranaceus L. (polysaccharides, flavonoids, saponins, aminoacids).

In particular, when the composition according to the present invention is for use in treatment of vitiligo in preparations for external use, said active substance 6 is selected from the group comprising the furanochromones, preferably is Visnaga daucoides (Khellin, Visnagin).

In particular, when the composition according to the present invention is for use in treatment of vitiligo and psoriasis in preparations for internal use, said active substance 6 is selected from the group comprising the Polyphenols, preferably is

Vitis Vinifera L, (Resveratrol).

Said neurogenic anti-inflammatory substance 4, said antioxidant substance 5 and said active substance 6 are in the ratio 1 : 1 : 0.04 by weight.

The described composition can be usefully employed, in combination with pharmaceutically acceptable excipients, for pharmaceutical preparations in the form of, for example, cream, lotion, gel, ointment, cutaneous solution, suspension, spray, foam, bath additive, colloid, impregnated dressing or medicated plaster.

The present invention is hereinafter described in more detail and specifically with reference to some examples, which are not to be construed as limiting the present invention.

Examples

Example 1: composition comprising an active substance conveyed through a biodegradable non-ionic nanovector.

Using a known amount of 100 mg of Resveratrol purified to 90%, extracted by forced percolation according to the methods indicated by the "VIII Italian Pharmacopoeia" and especially according to the guidelines published by Paul H. List and Peter C. Schmidt in the text "Drugs of vegetable origin" Hoepli Edition 1989 p. 131 and subsequents, titrated with HPLC (High Performance Liquid Chromatography) and standardized in cold chamber for 20 days at a temperature of 4 °C and with subsequent filtration with plates filter, the preparation of 50 g of product is carried out by means of a physical process of size reduction of the active substance where necessary (as to the raw material herein used, the initial size does not require such operation, such size being 1.08 x 0.35 nm; therefore, in the specific case, only the coating explained hereinbelow will be applied) by using a turbine mixer (which is a prototype machine entirely designed and constructed for the purposes of the present invention) and not through sintering.

The following step - i.e. coating or encapsulation - takes place through the emulsion at a temperature of 60 °C, by atomizing 30 mg of beeswax in the treated mixture; thereafter the temperature is lowered to 5 °C in 15 minutes in order to fix the coating material.

The last step of the production process is the purification of the obtained preparation through filters made in nanoceramic material, namely through cylindrical filters in glass and ceramics, with a mesh size not higher than 200 nm.

As far as the chemical-physical properties of the solution according to the present Example 1 are concerned, said solution is a straw-colored oily liquid with pH 7.0. It is worthy to note that, as regards the use of the other substances considered in the present invention (i.e., for example, Genistein and Capsaicin), the method of preparation is the same as shown hereinabove and nothing varies between a composition and the other one.

Example 2; composition comprising an active substance conveyed through a manipulated nanovector.

Using a saturated solution of nanovectors containing Resveratrol, prepared with the method described in Example 1 above, a further size reduction of the nanovector itself from 180 nm to 80 nm is carried out. This reduction occurs by deteriorating the coating wrap through a thermal shock at medium temperature (starting from a temperature of 5 °C, a temperature of 50 °C is reached in 3 minutes) carried out in a turbine dynamizator at variable pressure (which is a prototype machine entirely designed and constructed for the purposes of the present invention).

The preparation thus obtained is processed following the steps described in Example 1 above, used for the preparation of the biodegradable nanovectors, The purification step will occur through a filter made in nanoceramic material_/ namely through cylindrical filters in glass and ceramics_/ with a mesh size not higher than 120 nm. As far as the chemical-physical properties of the solution according to the present Example 2 are concerned_/ said solution is a straw-colored oily liquid with pH 7.0. It is worthy to note that_/ as regards the use of the other substances considered in the present invention (i.e., for example_/ Genistein and Capsaicin)_/ the method of preparation is the same as shown hereinabove and nothing varies between a composition and the other one.

Example 3: pharmaceutical preparation in the form of cream for use in treatment of vitiligo.

The nanovectors prepared according to the Examples 1 and 2 above_/ which are in the liquid form and have a straw-colored appearance_/ are introduced in a water/ oil or oil/water preparation for external use at a controlled temperature between 30 °C and 35 °C_/ under vacuum conditions_/ and thoroughly mixed through turbines for creams production for 30 minutes at a counterclockwise rotation of 1_/500 revolutions per minute.

In said cream pharmaceutical preparation for the treatment of vitiligo_/ said nanovectors and said water/oil preparation for external use are in the ratio of 1 : 0.2 in parts.

In said cream pharmaceutical preparation in for the treatment of vitiligo_/ said nanovectors and said oil /water preparation for external use are in the ratio 1 : 0.5 in parts.

The pharmaceutical preparation of the present Example 3 is recommended for external use according to the following dosage: repeated skin applications throughout the day from 2 to 3 times a day. Example 4: pharmaceutical preparation in the form of gel for use in treatment of psoriasis.

The nanovectors prepared according to the Examples 1 and 2 above, which are in the liquid form and have a straw-colored appearance, are introduced in a gelling agent, for example xanthan gum, at low temperature, for example at a temperature between 20 °C and 40 °C, at atmospheric pressure, and thoroughly mixed through turbines for creams and gel production for 30 minutes counterclockwise at a rotation speed of 1,500 revolutions per minute.

In said gel pharmaceutical preparation for the treatment of psoriasis, said nanovectors and said gelling agent are in the ratio of 1 : 50 in parts.

The pharmaceutical preparation of the present Example 4 is recommended for external use according to the following dosage: repeated skin applications throughout the day from 2 to 3 times a day.

As is apparent from the foregoing, the invention provides a composition for the treatment of dermatological diseases, and the relative pharmaceutical preparation, which allow to achieve the following main advantages:

thanks to the use of an anti-inflammatory substance the cellular healing is obtained; thanks to the use of an antioxidant the cellular strengthening is obtained;

thanks to the use of an active substance conveyed through a biodegradable nanovector the ultimate and stable over time cure of the dermatological disease is obtained.

On the basis of the description above, it therefore is understood that the composition for the treatment of dermatological diseases, and the relative pharmaceutical preparation, according to the present invention, achieve the objects and realize the advantages previously mentioned.

It is clear, finally, that many other variants of the subject composition for the treatment of dermatological diseases, and of the relative pharmaceutical preparation, can be carried out without departing from the novelty principles inherent in the inventive idea.

Claims

1. A composition for use in treatment of dermatological diseases comprising:

a) a neurogenic anti-inflammatory substance (4),

b) an antioxidant substance (5)_/ and

c) an active substance (6),

characterised in that at least one of said substances, preferably said active substance (6)_/ is suitable to be conveyed through a biodegradable nanovector (1).

2. A composition according to claim 1 for use in treatment of vitiligo and psoriasis.

3. A composition according to claim 1 or 2, wherein said biodegradable nanovector (1) is a biodegradable bilamellar non-ionic nanovector, or niosome.

4. A composition according to claim 1 or 2, wherein said biodegradable nanovector (1) is a manipulated nanovector.

5. A composition according to claim 1 or 2, wherein said neurogenic anti-inflammatory substance (4) is selected from the group comprising NSAIDs (Non-Steroidal Anti- Inflammatory Drugs) of vegetable origin.

6. A composition according to claim 5, wherein said neurogenic anti-inflammatory substance (4) is a vanilloid, preferably Capsaicin.

7. A composition according to claim 1 or 2, wherein said antioxidant substance (5) is selected from the group comprising Polyphenols of vegetable origin.

8. A composition according to claim 7, wherein said antioxidant substance (5) is Resveratrol.

9. A composition according to claim 1 or 2, wherein said active substance (6) is selected from the group comprising the Prostaglandin D2 inhibitors and/or enhancers of the Prostaglandin E2 effects.

10. A composition according to claim 9, wherein said active substance (6) is Genistein.

11. A composition according to claim 9, wherein the composition is for use in treatment of psoriasis in preparations for internal and external use and wherein said active substance (6) is selected from the group comprising the immunomodulators, preferably is Astragalus Membranaceus L..

12. A composition according to claim 9, wherein the composition is for use in treatment of vitiligo in preparations for external use and wherein said active substance (6) is selected from the group comprising the furanochromones, preferably is Visnaga daucoides.

13. A composition according to claim 9, wherein the composition is for use in treatment of vitiligo and psoriasis in preparations for internal use and wherein said active substance (6) is selected from the group comprising the Polyphenols_/ preferably is Vitis Vinifera L..

14. A composition according to any of the preceding claims, wherein said neurogenic anti-inflammatory substance, said antioxidant substance and said active substance are in the ratio 1 : 1 : 0.04 by weight.

15. A pharmaceutical preparation comprising the composition according to any of the preceding claims in combination with pharmaceutically acceptable excipients.

16. A pharmaceutical preparation according to claim 15 in the form of cream, lotion, gel, ointment, cutaneous solution, suspension, spray, foam, bath additive, colloid, impregnated dressing or medicated plaster.