Composition for topical use as an adjuvant in the prevention and treatment of seborrhoeic dermatitis

Abstract

Topical composition comprising a combination comprising a) Phosphatidylglycerol b) Propanediol caprylate and at least one dermatologically or cosmetically acceptable excipient, for use as an adjuvant for the prevention and treatment of seborrhoeic dermatitis, and in the treatment and prevention of dandruff.

Description

[0001] TITLE: "Composition for topical use as an adjuvant in the prevention and treatment of seborrhoeic dermatitis."

[0002] DESCRIPTION

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to compositions comprising functional substances with antimicrobial, purifying and rebalancing action on the skin barrier.

[0005] STATE OF THE ART

[0006] Seborrhoeic dermatitis (SD) is an inflammatory skin disease and a subtype of eczema with significant physical, psychosocial and economic repercussions. It is characterized by papulosquamous erythematous lesions in sebum-rich areas such as the face, scalp and upper chest. It has a chronic-relapsing pattern and its incidence peaks during three age periods: in the first three months of life, during puberty and in adulthood, with a peak at 40-60 years. The infantile form is self-limiting (what is known as cradle cap resolves within the first year of life), while the adult form has a chronic trend and seems to mainly affect the male sex.

[0007] The entire spectrum of SD, including dandruff localized in the scalp, is estimated to affect half the world population [Borda LJ, et al. Seborrheic dermatitis and dandruff: a comprehensive review. J Clin Investig Dermatol 2015; 3: 10], Despite such a high prevalence, the exact etiopathogenesis of SD remains unclear, as do the epidemiological data for the uncertain nosographic framing of some of its manifestations.

[0008] SD appears to have an increased prevalence in a number of neurological and psychiatric conditions. In fact, about 52-59% of Parkinson's disease patients have seborrhoeic dermatitis. It is also more common in immunosuppressed subjects (lymphoma, organ transplantation, HIV), suggesting that immune mechanisms are important in the pathogenesis of the disease, perhaps allowing the hyper-proliferation of Malassetia.

[0009] Despite being a localized dermatitis on areas particularly rich in sebaceous glands, it is possible that SD develops on subjects who have normal sebum production, just as subjects with excessive sebum production do not necessarily develop SD [Ro BI, Dawson TL. The role of sebaceous gland activity and scalp microfloral metabolism in the etiology of seborrheic dermatitis and dandruff. J Investig Dermatol Symp Proc 2005;10: 194-7], These data suggest that while sebaceous gland activity is strongly correlated with SD, sebum production alone is not decisive. In addition to the level of sebum production, alterations in lipid composition may also play a role in the development of SD, probably creating a favourable environment for the growth of the yeast Malassetia.

[0010] Historically, many researchers have theorized a central and causal role for Malassetia spp. In fact, numerous studies report an increase in the proliferation of Malassetia in skin areas affected by seborrhoeic dermatitis. Through specific enzymes called lipases, Malassetia degrades the skin's sebum to form fatty acids and peroxidised lipid derivatives. These substances irritate the skin and contribute to triggering the signs of the disease. Malassetia degrades sebum triglycerides to obtain fatty acids, which are essential for the production of cell membranes. Unlike other microorganisms, it cannot produce these fatty acids on its own.

[0011] Other studies instead show that there is no real increase in colonization by Malassetia with respect to healthy subjects, but rather a different virulence of the species. The fact is that, in the treatment of seborrhoeic dermatitis, molecules with antifungal action are very effective. Furthermore, recent studies have shown that, with respect to healthy subjects, those affected by this type of dermatitis show an increase in the proliferation of the Staphylococcus species in parallel with a decrease in the proliferation of Cutibacterium [Christy H.C. et al. More yeast, more problems?: reevaluating the role of Malassetia in seborrheic dermatitis. Archives of Dermatological Research (2024) 316: 100],

[0012] Recently, however, it has emerged that the dysregulation of the host immune system and the epidermal barrier, as in other eczemas, are key elements in the etiopathogenesis of SD.

[0013] Dandruff is associated with a decrease and alteration of the lipids that make up the stratum corneum, with consequent impairment of the structural integrity of the skin barrier, abnormal keratinization and therefore desquamation. The increase in TEWL (Trans Epidermal Water Loss) and the alteration in the composition of ceramides, which has also been observed in the presence of SD, is further confirmation of a weakened skin barrier. On the one hand, the alteration of the epidermal barrier causes the activation of the immune system and the production of cytokines, on the other hand, the increase in sebum secretion is a response to the alteration of the skin barrier and the desquamation process, creating an environment favourable to the abnormal proliferation of Malassetia. As regards altered ceramide composition, it appears that in seborrhoeic skin there is an increase in CerfNS] and CerfAS] and a significant reduction in CerfNdS], CerfEOS], CerfNP], Cer[NH], CerfAP] [Jannik R. Lesional skin of seborrheic dermatitis patients is characterized by skin barrier dysfunction and correlating alterations in the stratum comeum ceramide composition. Experimental Dermatology. 2024;33:el4952],

[0014] The main goal of seborrhoeic dermatitis (SD) therapy is to eliminate the visible signs of the disease and to reduce the symptoms, especially itching. A further important objective is to reduce the psychological distress that can be caused by the disease. Patients must be informed that SD is a chronic-relapsing condition and that there is no definitive therapy. Furthermore, patients should be advised to avoid, as far as possible, the triggers of SD (in primis the stress) and irritation of lesions induced by scratching or by the use of keratolytics.

[0015] A topical treatment is sufficient in most cases: the available therapies comprise topical products with antifungal or anti-inflammatory or keratolytic action containing, for example, pyroctone olamines, climbazoles and capryloyl glycines.

[0016] Dermocosmetic products play a key role in the long-term management of this disease:

[0017] - In the acute phase, they are able to aid and complete the action of the drug

[0018] - In the remission phase, they are specifically formulated products and therefore favour barrier balance maintenance, preventing exacerbations and the physiological microbial environment

[0019] - In mild forms, they allow symptoms to be managed, improving the appearance of the skin and consequently the psycho-physical state of the subject.

[0020] SUMMARY OF THE INVENTION

[0021] The Applicant has now surprisingly found that a topical composition comprising: a) Phosphatidylglycerol b) Propanediol caprylate and at least one dermatologically or cosmetically acceptable excipient and / or vehicle is particularly suitable for preventing and / or treating seborrhoeic dermatitis.

[0022] Preferably the amount of a)+b) is comprised between 0.30% and 1.5% by weight on the total weight of said composition.

[0023] Preferably, the ratio of a) / b) is comprised between 0.01 and 0.5, more preferably between 0.02 and 0.2.

[0024] The topical compositions according to the present invention can contain, in addition to the aforesaid active ingredients, also at least one Ceramide, an antimicrobial ingredient selected from Caprylyl glycol and Capryloyl glycine and mixtures thereof.

[0025] Such topical compositions can advantageously be used for the treatment and prevention of dandruff or as adjuvants for the treatment and prevention of seborrhoeic dermatitis, where for the purposes of the present invention the definition of adjuvant means that such compositions can be used in all three of the following situations:

[0026] - in the acute phase to complete the action of the drug;

[0027] -in the remission phase to promote barrier balance maintenance, preventing exacerbations and the physiological microbial environment

[0028] - in mild forms to allow better management of symptoms, improving the appearance of the skin and consequently the psycho-physical state of the subject.

[0029] DETAILED DESCRIPTION OF THE INVENTION

[0030] For the purposes of the present invention, the definition “comprising” does not exclude the presence of other components than those mentioned after such a definition.

[0031] The definition "consisting of’ excludes the presence of additional components listed after such a definition.

[0032] With the term "active ingredient" or "active" or "functional active", any ingredient, molecule, substance or mixture of compounds can be defined, capable of measurably stimulating a change in one of the skin parameters being evaluated, where such changes are significantly different from the application of the vehicle alone.

[0033] The topical compositions according to the invention also contain at least one cosmetically and dermatologically acceptable excipient and / or vehicle. For the purposes of the present invention, the definition of "at least one cosmetically or dermatologically acceptable excipient and / or vehicle" means that the at least one excipient and / or vehicle is suitable for topical application to corneal tissue, has good aesthetic properties, is compatible with the active ingredients of the present invention and any other components, and does not pose safety risks or concerns about toxicity.

[0034] The term cosmetic vehicle is intended as the set of excipients that contribute to the cosmetic formulation and can affect the skin permeability of the active ingredients.

[0035] It should be considered that even a simple "vehicle" without active ingredients is not a completely inert cosmetic product.

[0036] The synergy between vehicle and active ingredients is not predictable in advance and the choice of the right vehicle guarantees / supports the effectiveness and stability of the cosmetic product as a whole.

[0037] The term "topical composition" or "topical composition for cosmetic use" means, for the purposes of the present invention, various types of products such as: water-in-oil emulsions, oil-in-water emulsions, lotions, hydroalcoholic lotions, skin gels and oils, beauty soaps, deodorant soaps, bath and shower preparations (salts, foams, oils, gels), hair removal products, deodorants and antiperspirants, hair cleansing products (lotions, powders, shampoos), products for the hygiene of the body, teeth and mouth, products for external intimate hygiene, sun products.

[0038] The stability of the active ingredients used in a cosmetic formulation and the stability of the formulation itself, over time, contribute to the effectiveness of the formulated product.

[0039] In order to obtain a stable product, the cosmetic formulator evaluates and monitors, in its normal product preparation activity, both in the prototyping phase and in the industrial scale- up phase, some aspects such as: the presence of air bubbles in the formula, the emergence of oils, colour and / or odour change, pH changes, important viscosity changes.

[0040] For the purposes of the present invention, the term "antimicrobial ingredient" is intended as a cosmetic grade ingredient that has an antimicrobial efficacy (active towards Gram + / - bacteria, yeasts and moulds) and protective of the cosmetic composition. The exact etiopathogenesis of SD is not clear, but the applicant considered that the restoration / rebalancing of the skin barrier may be an interesting approach for the treatment of SD, together with obtaining a product with antimicrobial and anti-inflammatory action.

[0041] For the development of the present invention, therefore, the applicant started from the need to formulate a product which was effective in treating and / or preventing the manifestations related to skin affected by seborrhoeic dermatitis, in which the inflammatory process triggered by the presence of Malassetia could induce a subsequent weakening of the skin barrier, creating a self-propagating vicious-inflammatory cycle.

[0042] To this end, the applicant has identified a list of ingredients that could carry out such a task and in particular has studied a topical composition comprising a combination comprising a) Phosphatidylglycerol b) Propanediol caprylate and at least one dermatologically or cosmetically acceptable excipient.

[0043] Propanediol Caprylate is an ester and, like the triglycerides present in sebum, can be metabolised by the lipases of Malassetia. If the yeast degrades from the Propanediol Caprylate, two products will form: propanediol and caprylic acid.

[0044] The caprylic acid produced by the degradation by Malassetia is toxic to the yeast itself. By degrading Propanediol Caprylate, the true active molecule is therefore formed, consisting of caprylic acid that limits the proliferation of the yeast itself.

[0045] Propanediol caprylate is a raw, cosmetic grade material commercially available under the trade name CRINIPAN® PMC Green: it appears as a clear colourless or pale yellow liquid. Phosphatidylglycerol is a molecule of natural origin, with high dermocompatibility, as it faithfully reproduces molecules present in the skin.

[0046] It is commercially available as a raw, cosmetic grade material under the trade name BioSignal™ Lipid 10 MB.

[0047] The topical compositions which are the subject of the invention can comprise a combination as active ingredient, in addition to the components a. and b., namely: c) at least one Ceramide d) An antimicrobial ingredient selected from Caprylyl glycol and Capryloyl glycine and related mixtures of these two active ingredients.

[0048] In particular, the antimicrobial ingredient selected from Caprylyl glycol and Capryloyl glycine and related mixtures carries out a role as an antimicrobial excipient and preservative, but can contribute to the formulation of a product for topical use that has a broad action on the etiopathogenetic process of seborrhoeic dermatitis, although not yet defined, and allows better management and prevention of the inflammatory state characteristic of such a disease. The ceramide or component c) is preferably selected from N-acetylfingosine (ceramide 2 or NS) or the amide of phytosphingosine with stearic acid (Ceramide 3 or NP), preferably it is the amide of phytosphingosine with stearic acid.

[0049] The topical compositions which are the subject of the present invention can optionally contain at least one further active ingredient selected from the class consisting of Piroctone olamine, Dipotassium glycyrrhizinate, Isopalmide, Niacinamide, Allantoin, Bisabolol, Undecylenoyl glycine, Climbazole and D-panthenol.

[0050] The attention for the cosmetic use of Phosphatidylglycerol arises from the fact that many studies have been carried out to investigate the action of this molecule in different skin conditions.

[0051] However, Phosphatidylglycerol is a raw material that comes in the form of a semi-solid paste which is difficult to process. The Phosphatidylglycerol is diluted in glycerin for ease of use in cosmetic formulations. A more easily handled viscous liquid is thus achieved.

[0052] Scaling-up or production on an industrial scale is achieved after extensive tests necessary for the development of the production method.

[0053] Product industrialization activities are among the most delicate and determine the success or failure of putting new products into production: only a thorough analysis of the influence of process variables on key product variables makes it possible to obtain a product with the desired intrinsic quality parameters (appearance, colour, odour, viscosity, pH).

[0054] First during the prototyping phase, and then also the industrialization of the formulas, the applicant has found some problems in the inclusion of the ingredient Phosphatidylglycerol in any type of formulation (detergents, shampoos, lotions, hydroalcoholic lotions, O / W emulsions, W / O emulsions).

[0055] Several tests were needed to identify the best conditions to obtain a formulation with a homogeneous appearance and with a stable structure over time.

[0056] In particular, the Applicant has identified that the addition of the component a) Phosphatidylglycerol was critical for the stability of the cosmetic system in formulation.

[0057] To understand the problem related to the inclusion of component a) in the formula, the applicant started from the formulation of an emulsion which, for a normal formulator, represents the "worst case" in terms of formulation complexity. In the common practice of preparing any water-in-oil (W / O) or oil-in-water (O / W) emulsion, the process can be generalized into at least 4 PHASES:

[0058] 1. HYDROPHILE - HYDROPHILIC PHASE (in this phase the hydrophilic substances are mixed)

[0059] 2. LIPOPHILIC - HYDROPHOBIC PHASE (substances that are in the solid state at room temperature, such as waxes, etc., are normally melted in this phase)

[0060] 3. JOINING THE HYDROPHOBIC AND HYDROPHILIC PHASES (actual formation of the emulsion)

[0061] 4. COOLING PHASE (necessary to add any other thermolabile ingredients and unload the mass produced)

[0062] The applicant prepared several preparations (according to a conventional procedure), in which each phase was conducted at specific temperatures:

[0063] 1. HYDROPHILE- HYDROPHILIC PHASE (T=80°C)

[0064] 2. LIPOPHILIC - HYDROPHOBIC PHASE (T=85°C)

[0065] 3. JOINING THE HYDROPHOBIC AND HYDROPHILIC PHASES (actual emulsion formation) (T comprised between 80°C and 105°C)

[0066] 4. COOLING PHASE (T comprised between 70°C and 30°C)

[0067] Table 1 shows the tests carried out for the formulation of an O / W emulsion and from which the correct insertion temperature of the Phosphatidylglycerol in the formula was identified. In the case of the emulsion, Propanediol caprylate was always inserted in the lipophilic phase, before joining the phases, at T=85°C.

[0068] As can be seen from the tests described in Table 1, the Applicant succeeded in his intention to produce a stable product comprising Phosphatidylglycerol and Propanediol caprylate only after identifying that for such compositions, the ingredient Phosphatidylglycerol must be added at 35°C in the mass also containing other ingredients, such mass being previously cooled to 40°C.

[0069] In the formulation of a lotion and a detergent and / or shampoo, slightly different phases are created with respect to those listed above for the emulsion, since in this type of formulations the lipophilic phase is not present.

[0070] For the production of the aforesaid formulations, the person skilled in the art will follow the normal practice of inserting the ingredients, for example as reported in "Beginning Cosmetic Chemistry"3rded. ISBN: 978-1-932633-53-5 or “Handbook of cosmetic science and Technology” 3rded. International Standard Book Number-10: 1-4200-6963-2 (Hardcover); International Standard Book Number-13: 978-1-4200-6963-1 (Hardcover).

[0071] For the purposes of the present invention, a lotion for cosmetic use is a formulation containing at least 25% V / V of alcohol (denatured alcohol, letter C, density=0.79g / ml) on the total volume of the lotion. Propanediol caprylate was inserted in the alcohol phase to achieve better mixing (which with the emulsion was obtained by bringing the mass to T=85°C).

[0072] In the shampoo, the formulation takes place at a temperature of less than or equal to 35°C and to facilitate the mixing of the Propanediol caprylate, the latter was inserted in a phase comprising an additional ingredient (Surfactant) that facilitates the insertion thereof in the final formulation (mixture of PEG-55 propylene glycol oleate, Propylene glycol, Aqua and sold under the trade name ANTIL® 141 LIQUID MB), with the aim of obtaining a homogeneous and transparent mixture.

[0073] Each formulation (emulsion, shampoo, hydroalcoholic lotion) was analysed to verify the physical-chemical characteristics, previously listed, necessary to have a stable product over time. In particular, the parameters: Appearance, Colour, Odour, Viscosity and pH. Such parameters are measured at the temperature indicated for unloading the product from the production machine.

[0074] The smell is defined as "Characteristic of raw materials" when a perfume has not been included in the formulation.

[0075] Some of these parameters require the use of laboratory instrumentation, the use of which is known to a person skilled in the art.

[0076] A Knick electronic pH meter model 911 was used for pH measurement.

[0077] The viscosity was determined with a "Brookfield viscometer" model RVDV-1, which has a kit consisting of five different impellers that allow the analysis of more or less viscous emulsions (Table 2).

[0078] The formulations thus obtained preferably have the following chemi cal -physical characteristics:

[0079] Therefore, a further object of the present invention is the process for preparing the topical compositions which are the subject of the present invention, comprising adding the component a) Phosphatidylglycerol at 35°C in the composition containing the component b).

[0080] Examples of preferred, but non-limiting, formulations are included.

[0081] In bold type, some active ingredients that may be present in the formula, in addition to those already listed, are listed by way of non-limiting example.

Claims

CLAIMS1. Topical composition comprising an association comprising a) Phosphatidylglycerol b) Propanediol caprylate and at least one dermatologically or cosmetically acceptable excipient and / or vehicle.

2. Composition according to claim 1, wherein the Phosphatidylglycerol is in a weight ratio with respect to said Propanediol caprylate comprised between 0.01 and 0.5, preferably between 0.02 and 0.2.

3. Topical composition according to claim 1 or 2, wherein the sum of the components a) and b) is comprised between 0.30% and 1.5% m / m on the total weight of the topical composition.

4. Topical composition according to any one of the preceding claims 1-3, further comprising c) at least one Ceramide d) an antimicrobial ingredient selected from caprylyl glycol and capryloyl glycine and mixtures of these two active ingredients.

5. Topical composition according to claim 4, wherein said ceramide or component c) is selected from N-acetylsphingosine (ceramide 2 or NS) or the amide of phytosphingosine with stearic acid (Ceramide 3 or NP), preferably it is the amide of phytosphingosine with stearic acid.

6. Topical composition according to any one of claims 1-5, in the form of oil-in-water or water-in-oil emulsions, shampoo, a detergent, a lotion, a hydroalcoholic lotion.

7. Topical composition according to any one of claims 1-6 for use in the treatment and / or prevention of dandruff and its formation.

8. Topical composition according to any one of claims 1-6 for use as an adjuvant in the treatment and prevention of seborrhoeic dermatitis.

9. Process for preparing the topical compositions according to any one of claims 1-3, comprising adding the component a) Phosphatidylglycerol at 35°C in the topical composition containing the component b) and any optional active ingredients according to any one of claims 4-5.

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