WO2016181355A1

WO2016181355A1 - Compositions for treating and/or preventing psoriasis, prickly heat, dermatitises, neurofibromatosis type 1 and other pathologies of the dermis, mucosae, and oral cavity

Info

Publication number: WO2016181355A1
Application number: PCT/IB2016/052770
Authority: WO
Inventors: Roberto Logi
Original assignee: Roberto Logi
Priority date: 2015-05-14
Filing date: 2016-05-13
Publication date: 2016-11-17
Also published as: TN2017000478A1; EP3294267A1

Abstract

Compositions for treating and/or preventing psoriasis, prickly heat, dermatitises, neurofibromatosis type 1 and other pathologies of the dermis, mucosae, and oral cavity containing as active ingredients Croton lechleri resin extract and Melaleuca alternifolia essential oil in combination with possible other excipients.

Description

COMPOSITIONS FOR TREATING AND/OR PREVENTING PSORIASIS, PRICKLY HEAT, DERMATITISES, NEUROFIBROMATOSIS TYPE 1 AND OTHER PATHOLOGIES OF THE DERMIS, MUCOSAE, AND ORAL CAVITY

Field of the invention

Psoriasis, prickly heat, dermatitises, neurofibromatosis type 1 and other pathologies of the dermis, mucosae, and oral cavity

State of the art

In the Western countries, psoriasis has rates ranging between 1.4% and 4.82% of the population, with values higher in the countries of the Northern Europe with respect to the countries of the Southern Europe. It affects both sexes, even if women get sick earlier. In Italy, psoriasis prevalence reaches the value of 3.1%, thus representing one of the more frequent skin diseases .

The available data seem to suggest that the disease differs not only depending on the age group, normally between 10 and 40 years, but also the geographic region, with a tendency to higher frequency in those countries far from the equator.

The etiology of psoriasis is still unknown. To date, it is believed that genetic factors, immune factors, environmental factors and infectious factor are involved in the psoriasis. Currently, there are two main hypothesis related to the process occurring in the development of the disease. According to the first hypothesis - hyperkeratinic hypothesis - the psoriasis is considered as a disorder of the excessive growth and reproduction of the skin cells. The problem is considered as a disorder of the epidermis and keratinocytes .

The second hypothesis - of immune-mediated disorder - considers that the excessive reproduction of the skin cells is a consequence of various factors produced by the immune system.

This hypothesis, that immune-mediated, was obtained by observing that the immunosuppressive drugs can reduce or resolve the psoriatic plaques.

However, the role of the immune system is not fully understood even if the compromise of the barrier function of the skin seems to have a primary role in the etiopathogenesis of psoriasis.

The treatment of psoriasis is based on a series of general measures which comprise a suitable topical hydration, suitable exposure to solar radiation and the use of tar-like substances and mineral oils. The treatment by systemic route is reserved to people suffering from severe or particularly diffuse forms, or to those patients for which topical or phototherapy treatments showed to be ineffective.

The main agents active against psoriasis by systemic route are methotrexate, cyclosporin A and retinoids (acitretin and etretinate) , all drugs that unfortunately have adverse effects, some of which are serious .

Biological drugs currently represent the new drug frontier in the field of psoriasis.

The affirmation of these new therapies lies in their selectivity of action which allows to obtain, in most cases, a therapeutic efficacy without toxicity for the organs in the long-term treatment and a good tolerability .

The biological drugs produced so far, obtained through the recombinant DNA technologies, act on specific molecules activated in psoriasis, such as TNF-alpha or interleukin 12/23, as they selectively target one of the "vital centers" of the disease.

This drugs are monoclonal antibodies without organ toxicity in the long term. This means that once their administration is started, their suspension is not provided, unless adverse events, intolerance or ineffectiveness. The clinical history of neoplasia counterindicates however the use of biological drugs. Furthermore the effectiveness of these latter, in particular of the anti-TNF-alfa, is considerably reduced as for obese people. Finally, biological drugs unfortunately have a high cost which limit their spread .

Although biological drugs represent the prior art concerning the pharmacology related to psoriasis, they have problems with reference to the side effects, the use dosage which always requires an health worker, and high costs for the national health services.

Summarizing, therefore to date all the therapies for psoriasis known in the prior art have a low effectiveness, or serious side effects, or complex dosages or they are expensive.

The patent application WO 2011/148257 on behalf of the same Applicant it is described that the combined use for topical use of a Croton lechleri resin extract and Melaleuca alternifolia essential oil, allows an extremely quick cicatrisation of cutaneous ulcers, in particular chronic ulcers, such as for example decubitus ulcers, even more in particular trophic ulcers of the lower limbs, with the ensuing complete healing of said lesions; furthermore it is reported that the combined use as previously described allows resolving, within quick times (between 24 and 72 hours), the cutaneous ulcers caused by the Herpes simplex virus, in particular lip ulcers, also preventing relapses thereof, or the cutaneous ulcers that occur in form of Herpes zoster. Therefore the therapy proposed is effective in the field of ulcers for which etiologies are known: diabetic - vascular - from pressure - traumatic - from burn, and from herpes. But psoriasis, prickly heat, and almost all the dermatitises however have an etiology still unknown and above all a pathogenesis that is exactly opposite with respect to ulcers otherwise the hyperkeratosis, namely an increase in terms of skin thickness and of the corneous layer of epidermidis. Instead, as for the neurofibromatosis type 1 (NF1) there is the suspicion that it is a dominant autosomal genetic disease. Therefore, in view of the above, the use of the above- mentioned products for the therapy of these types of pathologies cannot be supposed.

Summary of the invention

Formulations comprising a Croton lechleri resin extract and Melaleuca alternifolia essential oil for use in the treatment of various types of dermopathies are described .

Brief description of the pictures enclosed.

Picture 1 shows the evolution of a case of psoriasis, from the beginning (A) and after 30 days of treatment (B) . Picture 2 shows the evolution of a case of early prickly heat (A) and after one week (B) .

Picture 3 shows a case of irritant dermatitis at the beginning (A) and after 2 months of treatment (B) .

Picture 4 shows an evolution of a case of nodule injured by neurofibromatosis type 1 at the beginning (A) and after twenty days of treatment (B) .

Detailed description of the invention

Contrary to what was possible to be hypothesized, it was surprisingly found that a composition as that described below not only is capable of speeding up the scarring processes, as indicated in the previous patent application, but also acting contrariwise, namely limiting and/or immunoregulating the hypersecretive processes.

Therefore the present invention allows to overcome the above-mentioned problems of current therapies (ineffectiveness, adverse effects, complex dosages, high costs) thanks to a composition containing as active ingredients Croton lechleri resin extract and Melaleuca alternifolia essential oil in the presence of other possible excipients currently used for the preparation of liquid or semi-solid solutions for topical pharmaceutical application, sprays, gels, roll- ons, plasters and medicated bandages, adhesive pastes, viscous solutions and mouthwashes.

The cases reported in the examples, although relating to different pathologies and etiologies unknown so far, for all show an undeniable effectiveness of the various compositions of the kit as skin-regulators, or as effective in the normoregulation of the integumentary system. Therefore, the present invention solves the indicated pathologies through a topical treatment, with a simple use dosage because of self-administered, without side effects, and low costs.

Furthermore, in order to achieve a better result and compliance of the patient, it is necessary to provide an analgesic therapy and this result was achieved as patients treated with the compositions of the kit in the various dermopathies (psoriasis, prickly heat, dermatitis, NF1, etc.) always reported pain or itching disappearance after few minutes, or few hours, from the first application.

According to the present invention, the formulation of various specific pharmaceutical forms further allows an easier management of the treatments by the patient and thus facilitating the self-administration for the home use. This allows a further reduction of the high costs that the national health services support for this type of cure which often requires the help of health workers.

Non-limiting examples of commonly used excipients can include: plasticizers as pomade or ointment based on Calendula officinalis, and/or a pomade or cream based on Hypericum perforatum, and/or a pomade or ointment based on Hamamelis Virginiana, emulsifiers as beta- glucans, glyceryl monolaurates and, for example purposes only, emulsifiers as sodium lauryl sulfate, stearyl alcohol, polysorbate 20-60-80, cetomacrogol (Codex) , Polyethylen glycol stearate called PEG 20-40- 60, Carbomer 934 P, Carbowax, Carbopol, glycerin, polysorbates also called Tween 20-40-60-80, alkyl polyglucosides , polyglycerol esters (non-ethoxylated) , and other surfactants and/or thickeners such as Resassol VH, Natrosol, Montanox, Tegosolve, polycanol and similar.

Preferably, the Croton lechleri resin extract used in the kit of parts object of the present invention is a liquid solution of resinous latex, 100% of plant origin, of the Croton Lechleri plant being at least 5 years old, and even more preferably it is a liquid solution of Croton lechleri pure resin extracted into 10% alcohol or it is a liquid solution of Croton lechleri pure resin in 1:10 dilution in hydro-glycero- alcoholic solution.

Preferably, Melaleuca alternifolia oil used in the kit of parts object of the present invention is a 100% essential oil.

The Croton lechleri resin extract/Melaleuca alternifolia essential oil ratio is normally comprised between 1:0.05 and 1:1.5.

The sum of the two active ingredients normally constitutes the 60-80% by weight based on the total weight of the formulation in the liquid and semi-solid pharmaceutical forms for topical use. However said sum can be reduced up to 0.2% in the pharmaceutical forms for oral use.

For example purposes only, some compositions according to the present invention are reported below.

Generally the amount by weight of the composition according to the invention, which is daily administered on the skin and oral cavity pathologies is comprised between 1ml and 15ml, preferably 10ml on the psoriatic plaques and spread dermatitises, 2.5ml on dermatitises and other cutaneous pathologies, 1 ml as for pathologies of the oral cavity.

It was surprisingly found, and it represents a further object of the present invention, that the compositions (new formulations) according to the present invention are useful for the treatment of other pathologies, not described and unpredictable based on what is known so far, because they have an unknown etiology.

In fact excellent healing results, as well as in the treatment of psoriasis, also as for the prickly heat, dermatitis and NF1, were obtained, as shown in the pictures enclosed.

Fast healing results were obtained also in the treatment of the actinic keratosis, acne, seborrheic dermopathies , lichen planus, lupus erythematosus and rosacea. Further studies with optimal results were further carried out in the wide field of the pathologies of the oral cavity, for illustrative, but not limiting purposes, the perioral dermatitis, oral candidiasis, oral lichen planus, periodontopathies, gingivitis and necrotizing periodontitis, and in the recurrent aphthous stomatitis. All pathologies for which to date there are few effective treatments validly recognized by the scientific community.

If necessary, the compositions can be applied by self- administration more times daily from one to four times, normally two times, through the pharmaceutical forms of the liquid solution, gels, plasters and medicated bandages, adhesive paste, viscous solution, mouthwash; the complete healing of the various pathologies occurs within a time range from 2 days to 4 months from the beginning of the treatment, depending on the seriousness of the pathology or the chronicity thereof. Examples

Example 1 - clinical case of psoriasis treated with the kit of the present invention

A 60 years old subject, being the subject of male sex, affected by psoriasis for 3 years, previously treated unsuccessfully with Psorcutan ( calcipotriol ) and an hydrating cream. Among the undesired effect of calcipotriol, the most frequently observed are: the appearance on the skin of cutaneous rash, erythema and contact dermatitis, but generally also pain, hypercalcemia, burning, skin atrophy, as well as having the limitation of the counterindication of the use in the skin folds. The subject begins the treatment - Picture 1 (A) - by applying two times daily the cream prepared with a formulation constituted by:

hydroalcoholic extract with 10% of

Croton lechleri resin 20% Melaleuca alternifolia essential oil 3% PPG-26 Buteth and Peg-40 hydrogenated castor oil 13% xantan gum 0.7% hydroxyethylcellulose for the pharmaceutical use 2% water q.s. to 100% After few hours from the first application the patient reports about analgesia and itching disappearance. After 30 days only - Picture 1 (B) - the dimension of the injury reduced, the furrows are less evident, the skin redness decreased, also the peeling is clearly decreased .

Example 2 - clinical case of prickly heat treated with the kit of the present invention

A 65 years old subject, being the subject of male sex, affected by prickly heat. The subject suffered from recurrent event of this pathology since he was five years old, normally such pathology manifests during the wet heat periods and in stress conditions lasting for about fifty days. The subject has prickly heat of the severe type, spread throughout the body and in particular the hit anatomical areas are: armpits, chest, back, inner thighs (groin) and ear. During the many years of relapses of this disease, the patient tried several products and all of them showed to be ineffective. Immediately after the beginning of the treatment - picture 2 (A) - based on a liquid solution composed by:

Croton lechleri 50% Melaleuca alternifolia 50% the patient referred about itching disappearance in the affected body areas and the desquamative phenomen stopped already after two days.

As showed in picture 2 (B) related to the end of the treatment, the new epithelium reformed in one week.

Example 3 - clinical case of irritant contact dermatitis treated with the kit of the present invention

A 60 years old subject, being the subject of male sex, affected by irritant contact dermatitis. All begins three years before due to a cut on the left thumb finger caused by an usb key, which contains nickel. The infection spreads in a first time on all the palm of the left hand and then also on the palm of the right hand. He was firstly treated for three years with various topical corticosteroids and then with homeopathic products, among which Valal cream, but without any success .

The patient had the following symptoms on both the hands: scaly dermatitis, severe itching, and small injuries caused by the treatment. The infection is spread all over the palm of the hand with a red coloring around the injuries, and in other points of yellowish color.

Furthermore, the nocturnal itching often cause insomnia to the subject and the serious limitation in the use of hands significantly reduced the social and working life of the subject in the last three years. Furthermore, after the delusion of the failures concerning all the tested therapies, the subject is depressed, obese and highly discouraged with respect to any treatment. After half an hour from the beginning of the treatment - Picture 3(A) - the itching disappeared. The subject was treated with the kit of the present invention and more precisely, with the semisolid pharmaceutical form of a gel, constituted by:

hydroalcoholic extract with 10% of

Croton lechleri resin 30% Melaleuca alternifolia essential oil 3% PPG-26 Buteth and Peg-40 hydrogenated castor oil 18% xantan gum 0.7% hydroxyethylcellulose 2% water q.s. to 100% The gel self-administered by the patient two times daily, in the morning and in the evening, in the amounts of about 1 ml per application, more preferably 2.5 ml dose die. Since the next day from the beginning of the treatment the epithelium gradually regenerated losing the squamous characteristics and a slow, but constant healing was observed. The patient, encouraged by the results of the therapy, after two weeks decided to start a diet in order to lose the weight put on in the preceding three years. The complete healing was obtained after two months - picture 3 (B) .

Example 4 - Clinical case of neurofibromatosis type 1 (NF1) treated with the kit of the present invention

A 53 years old subject, affected by the injury of a neurofibromatosis type 1 nodule since one year.

The subject suffered from this serious pathology since the childhood, having various neurofibromatosis nodules all over the body. Unfortunately the pathology increases with the age and currently there are no treatments recognized by the scientific community. The nodule on the forehead injured for one year and, in this period, various topical corticosteroids and cicatrizing were tested, but without positive results. A not-severe, but constant itching present in the peri-injured area caused problems of nocturnal awakenings and a general sense of physical discomfort to the subject.

Furthermore, as the nodule is well visible on the forehead, the patient also suffered from discomforts in the social relationship. Picture 4(A) shows the beginning of the treatment with a composition according to the invention formulated as a gel constituted by: hydroalcoholic extract with 10% of

Croton lechleri resin 50% Melaleuca alternifolia essential oil 3% PPG-26 Buteth and Peg-40 hydrogenated castor oil 18% xantan gum 0.7% hydroxyethylcellulose 2% water q.s. to 100%.

The gel self-administered two times daily, in the morning and in the evening, in the amounts of about 1 ml per application, more preferably 2.5 ml dose die. The patient referred about itching disappearance in the peri-injured area already after few hours after the first application and the injury, small but deep, healed in 20 days only, as showed in the picture 4 (B) .

Claims

1. A composition containing as active ingredients Croton lechleri resin extract and Melaleuca alternifolia essential oil in combination with any other excipients for use in the topical treatment of psoriasis, prickly heat, dermatitis, NF1, rosacea and oral diseases.

2. Compositions according to claim 1 wherein said formulations are in the form of sprays, gels, roll-ons, plasters and medicated bandages, adhesive pastes, viscous solutions and mouthwashes.

3. Compositions according to claims 1 and 2 wherein said excipients are selected from: elasticizers, emulsifiers, surfactants and/or thickeners.

4. Compositions according to claims 1 - 3 wherein said Croton lechleri resin extract used in the kit of parts according to the present invention is a liquid solution of resinous latex, 100% of plant origin, of the Croton Lechleri plant being at least 5 years old or a liquid solution of Croton lechleri pure resin extracted into 10% alcohol or a liquid solution of Croton lechleri pure resin in 1:10 dilution in hydro-glycero-alcoholic solution .

5. Compositions according to claims 1 - 4 wherein said Melaleuca alternifolia essential oil is a 100% essential oil.

6. Compositions according to claims 1 - 5 wherein the Croton lechleri resin extract/ Melaleuca alternifolia essential oil ratio is comprised between 1:0.05 and 1:1.5.

7. Compositions according to claims 6 consisting of: Croton lechleri resin extract 50%

Melaleuca alternifolia essential oil 50%

8. Compositions according to claims 1 - 7 in liquid and semi-solid form for topical use, wherein the sum of the two active ingredients is 60-80% by weight based on the total weight of the formulation.

9. Compositions according to claims 1 - 7 in a form suitable for oral use, wherein the sum of the two active ingredients is 0.2% by weight based on the total weight of the formulation.

10. Pharmaceutical formulations comprising a composition according to claims 1 - 7 in the form of: liquid solution, gels, plasters and medicated bandages, adhesive paste, viscous solution, mouthwash.