ES3030758A1 - Cosmetic or pharmaceutical composition for topical use, method of preparation and use thereof for the treatment of senile skin (Machine-translation by Google Translate, not legally binding) - Google Patents

Abstract

Cosmetic or pharmaceutical composition in the form of an oil-in-water emulsion, with an aqueous phase and a fatty phase, for topical use, characterized in that it comprises sodium hyaluronate, pumpkin seed protein hydrolyzate, panthenol, squalane, sodium stearyl lactylate as an anionic emulsifying agent and ammonium acryloyldimethyltaurate and vinylpyrrolidone copolymer, and in that it has a pH between 4.5 and 6.5. The composition according to the invention makes it possible to obtain an emulsion without phase separation and that is stable while maintaining the properties in its formulation. The invention also relates to a method for preparing the composition and to the use of the composition in the treatment of senile skin.

Description

DESCRIPTION

COSMETIC OR PHARMACEUTICAL COMPOSITION FOR TOPICAL USE, METHOD OF

PREPARATION AND USE OF SAME FOR TREATMENT OF SENILE SKIN

Field of the invention

The invention relates to a cosmetic or pharmaceutical composition in the form of an oil-in-water emulsion, comprising an aqueous phase and a fatty phase, for topical use. The invention also relates to a method for preparing said composition and its use in the treatment of senile skin.

State of the art

The skin is usually divided into three main layers: the outer layer (epidermis) contains skin cells, pigments, and proteins. The middle layer (dermis) contains blood vessels, nerves, hair follicles, and sebaceous glands. The dermis provides nutrients to the epidermis. Finally, the inner layer (the subcutaneous layer) contains sweat glands, some hair follicles, blood vessels, and fat.

During normal aging, the epidermis thins and moisture levels decrease. Changes in connective tissue reduce skin strength and elasticity due to the degradation and loss of collagen and elastin. Blood vessels in the dermis become more fragile. The subcutaneous fat layer thins over time. Therefore, aging skin repairs itself more slowly.

Skin aging is a physiological process characterized by thin, dry skin, the appearance of wrinkles, loss of elasticity, and exaggerated skin fragility, with frequent bruising. This manifests as atrophy of the skin and what is known as dermatoporosis or chronic skin insufficiency. It affects one in three people over the age of 60, and its incidence increases with age, primarily manifesting in areas exposed to light.

The skin's barrier function is reduced, decreasing its resistance to trauma, sensitization to stimuli, protective elasticity against friction, impermeability to external aggressions, in addition to the antimicrobial function performed by the hydrolipidic film.

All of the aforementioned processes are more pronounced in senile or elderly skin. This is an extremely thin, delicate, and fragile skin, where the loss of hydration and elastin and collagen fibers is more pronounced, resulting in atrophy due to increased skin aging. Itching is very common, probably linked to exacerbated dryness, with a parchment-like feel, as well as extreme skin and capillary fragility, leading to the frequent presence of bruises or purpura and wounds. This atrophy is particularly prevalent on the neck, hands, arms, and legs.

For general skin aging, cosmetic and pharmaceutical remedies, as well as bibliographic references, are abundant in active ingredients and compositions for the treatment of wrinkles, symptoms of dryness, tears and wounds, blemishes, etc., and in general, the symptoms and manifestations of skin atrophy.

For example, formulations in the form of lotions, emulsions, gels, suspensions, dispersions, aerosols, powders, etc., are well-known, which contain as active substances humectants, moisturizers, emollients, chemical and physical exfoliants for peeling, antioxidants, free radical reducers, etc.

Treatments for wrinkles, both physical and chemical, are highly developed; however, in the case of senile skin, this is not a target of interest, since skin atrophy, dermatoporosis, functional insufficiency, etc., lead to manifestations and symptoms for which the wrinkle is of no importance.

The quantity and variety of preparations present in dermopharmacy and in the field of cosmetics, shows that, research and development related to cosmetic and pharmaceutical formulations related to skin aging, both for adult skin and senile skin, is a field of interest, current, important and open to new stable formulations that provide advantages over those already known and that maintain or improve the effectiveness in the treatment of atrophic skin, giving trophism, that is, density, thickness, hydration, resistance, toning, functionality, etc.

It is common to use several active ingredients, either in separate formulations or in the same formulation, to effectively address the various manifestations of senile atrophic skin. The use of separate formulations increases the cost and time of treatments, as does layered application; while, conversely, simultaneous and homogeneous application, as well as cost and time, are very advantageous in formulations containing multiple active ingredients.

However, the formulation of active ingredients with different functional groups that exhibit distinct chemical characteristics often presents compatibility problems, which can lead to a lack of stability, both chemically and physically, and even deficiencies in the expected activity on the skin.

Exposition of the invention

The invention aims to provide a composition of the type indicated at the beginning, in which in the final formulation the interactions between the active ingredients do not give rise to the formation of precipitates and, depending on the components of the desired emulsion, without phase separation and stable, and which also allows the effective treatment of senile skin.

This purpose is achieved by a composition of the type indicated at the beginning, characterized in that it comprises

- sodium hyaluronate,

- pumpkin seed protein hydrolysate,

- panthenol,

- squalane,

- sodium stearyl lactylate as an anionic emulsifying agent, and

- ammonium acryloyldimethyltaurate and vinylpyrrolidone copolymer as an anionic rheology modifying agent; and

because it has a pH between 4.5 and 6.5.

Sodium hyaluronate, and the corresponding hyaluronic acid, is a natural polysaccharide of the glycosaminoglycan type composed of alternating residues of D-glucuronic acid and N-acetyl-D-glucosamine, which has a structural function. It is a linear polymer with a molecular weight, depending on the source and production method, between 50,000 and 15,000,000 daltons (Da). It is present in all living organisms and is a universal component of the extracellular space in tissues, including the skin, constituting a matrix that allows lubrication, absorption, transport of nutrients to cells, and elimination of waste from them. Hyaluronic acid plays a decisive role as a connective tissue element, being an essential element in the skin, with approximately 50% of the hyaluronic acid concentration in the body. Its moisturizing and film-forming properties make it particularly useful for treating senile skin, preventing water loss from the epidermis and dermis.

The protein fraction of pumpkin seeds or protein hydrolysate of pumpkin seeds, is a highly moisturizing agent with other types of mineral and lipid active ingredients, in addition to containing all the essential amino acids, which acts by promoting collagen synthesis and preserving the network of elastic fibers and collagen itself in the skin, thus contributing to improving or enhancing skin elasticity or skin tone and, therefore, improving the biomechanical properties of the skin.

Panthenol, in addition to its recognized moisturizing properties, itching relief and interaction with skin lipids, several studies show that it helps the skin repair itself by stimulating the production of cells present in the skin whose action is known in wound healing (Weiser and Erlemann 1987, Weimann IB, Hermann D. Int.J.Vitam. Nutr. Res. 1999, 69: 11319 and Marquardt Y.et al.Lasers. Surg. Med. 2015; 47/257-265).

Squalane is a fat-soluble plant-derived emollient, and is therefore incorporated into the fatty phase of the emulsion. It is a highly refined plant lipid with a molecular structure very similar to that of skin lipids and can presumably fuse with the epidermal lipids of the stratum corneum, reinforcing the skin's barrier function, reducing transepidermal water loss (TEWL), and providing emollience and softness to the skin.

Regarding the chemical characteristics of the active ingredients, sodium hyaluronate is the sodium salt of hyaluronic acid, a polysaccharide of the glycosaminoglycan type, composed of repetitive polymeric disaccharides of D-glucuronic acid and N-acetyl-D-glucosamine. It therefore contains both free and salified acid groups. The protein fraction of pumpkin seeds is a hydrolyzed pumpkin seed and therefore contains a high number of amino acids and their corresponding amino and carboxylic residues. Panthenol is a relatively small molecule that lacks ionic groups, but does have hydroxyl and amide groups that make it insoluble in fats. Squalane is a hydrocarbon. These emollients are fatty and hydrocarbon-like and, therefore, are not miscible or soluble with polar or ionic substances.

Therefore, acid-base interactions and/or a lack of miscibility between the active ingredients in the formulation can be expected, which can alter the composition's stability and efficacy as a result of the potential formation of precipitable simple or complex salts or phase formation. In other words, active ingredients, although desirable given their number and chemical nature, present challenges when formulating them in a single composition.

In fact, when formulated directly in water, without the presence of pH modifiers or in the absence of emulsifiers or rheology modifiers, the formulation at the desirable concentrations of the active ingredients, for example preferably between 0.01% and 0.5% by weight of sodium hyaluronate; preferably between 1.0% and 8.0% by weight of pumpkin seed protein hydrolysate; preferably between 0.1% and 2.0% by weight of panthenol, and preferably between 0.5% and 5.5% by weight of squalane, has at least two phases, or even a solid phase depending on the concentrations used. This highlights that the interaction of the different acidic and basic groups and/or the different solubility or miscibility of the active ingredients make the formulation incompatible with such a number of active ingredients with different chemical natures in the desired proportions. Adjusting the pH with acid modifiers to slightly acidic values, compatible with the skin's pH, also does not solve the problem of homogeneity of the desired formulation.

On the other hand, the use of emulsifiers, neither non-ionic nor ionic-cationic, at the desired pH, does not solve the problem of obtaining a stable formulation with a pH between 4.5 and 6.5. Only anionic emulsifiers allow a formulation with the desired homogeneity and stability and, more specifically, sodium stearoyl lactylate alone or mixed with other non-ionic emulsifiers, but, surprisingly, always with the presence of sodium stearoyl lactylate.

Furthermore, to stabilize the emulsion by increasing its viscosity, as with the emulsifier, an ionic rheological modifier is also required, with the function of a thickening agent or consistency regulator, but also, surprisingly, of an anionic type and, more specifically, a copolymer of ammonium acryloyldimethyltaurate and vinylpyrrolidone, alone or mixed with other non-ionic types, but, surprisingly, always with the presence of the copolymer of ammonium acryloyldimethyltaurate and vinylpyrrolidone.

Research and development work has ultimately led to the development of a composition of four active ingredients formulated within a narrow, specific pH range, containing an anionic ionic emulsifier and an anionic ionic rheological modifier. This composition exhibits excellent stability, with no precipitation of saline-type solids or complexes resulting from potential interactions between active ingredients with distinct chemical natures. In addition to stability, it exhibits desirable pharmacotechnical and organoleptic characteristics, providing the desired trophism for application to senile skin, as demonstrated by the results of the clinical study conducted and presented in this invention on symptoms such as atrophy, wrinkles, fragility, dryness, pruritus, wounds, and purpura.

Thus, a technical solution is proposed in the formulation of four active components, according to which, the invented formulation and composition, in the form of an oil-in-water emulsion for application to the skin, containing sodium hyaluronate, pumpkin seed protein hydrolyzate, panthenol and squalane, formulated in a specific pH range and with an anionic emulsifier and an anionic rheological modifier, also specific, so that it remains stable and presents physicochemical characteristics suitable for application to the skin, and which allows for the availability of a product that provides trophism to atrophic senile skin.

A stable cosmetic or pharmaceutical composition is thus available for treating senile skin based on sodium hyaluronate, pumpkin seed protein hydrolyzate, panthenol and squalane for application to skin that possibly presents synergy or, at least, improves the trophism of aged skin in its different degrees as demonstrated, for example, in the clinical study carried out with an exemplary embodiment of the composition and described below.

Another object of the invention is to provide a method for preparing a composition according to the invention, characterized in that it comprises the following steps:

a) preparing a first aqueous phase comprising said sodium hyaluronate and said pumpkin seed protein hydrolysate as ionic active ingredients;

b) incorporating into said first aqueous phase said panthenol, preferably dissolved in water, as a non-ionic active ingredient;

c) preparing a fatty phase comprising said sodium stearoyl lactylate as an anionic emulsifying agent and said squalane as a humectant;

d) lastly adding all the ammonium acryloyldimethyltaurate and vinylpyrrolidone copolymer as an anionic rheological modifier to the fatty phase;

e) emulsifying said first aqueous phase and said fatty phase by adding said fatty phase to said first aqueous phase, obtaining an emulsion;

f) if necessary, adjust the pH, using a pH adjusting agent, to a value between 4.5 and 6.5, preferably between 5.0 and 6.0.

Another object of the invention is to provide a composition obtainable by the method according to the invention.

It should be noted that the method according to the invention, characterized by the preparation of different independent phases containing the components indicated for each phase, and that these are incorporated into the process strictly in the sequential order described, is advantageous for obtaining a composition in which interactions between the active ingredients do not give rise to the formation of precipitates and, depending on the components of the desired emulsion, without phase separation and stable. Furthermore, it allows obtaining a composition with a pleasant texture that facilitates both its application to the skin and improved adherence to the treatment due to an improved end-user experience.

Another object of the invention is to provide a composition according to the invention for use in the treatment of senile skin. This results in an advantageous application thereof.

The present invention provides a composition in the form of an oil-in-water emulsion, containing four active ingredients formulated in a specific pH range and an emulsifier of ionic type, more specifically of anionic type, and a rheological modifier as a stabilizer, also of ionic type and, more specifically, also of anionic type so that it is stable and has physicochemical characteristics, particularly pH, suitable for its application, fundamentally, in addition to the neck and hands, in large areas such as legs and arms.

In particular, the present invention provides a composition in the form of an oil-in-water emulsion, containing four active ingredients formulated in a specific pH range and, with at least, one emulsifier and one anionic stabilizer, in particular sodium stearoyl lactylate and ammonium acryloyldimethyltaurate and vinylpyrrolidone copolymer, so that it is stable and has physicochemical characteristics, particularly the pH, suitable for application to skin, which allows high hydration, also favoring collagen synthesis and enhancing skin elasticity, thus giving trophism to senile skin, mainly on the neck, hands, and large areas such as legs and arms.

Furthermore, the present invention provides a composition in the form of an oil-in-water emulsion, containing four active ingredients formulated in a specific pH range and with at least one emulsifier and one anionic stabilizer, in particular sodium stearoyl lactylate and ammonium acryloyldimethyltaurate and vinylpyrrolidone copolymer, so that it is stable and has physicochemical characteristics, particularly the pH, suitable for application to skin, which allows its use on atrophic, dry and fragile senile skin.

Furthermore, the invention encompasses a number of preferred features which are the subject of the dependent claims and whose usefulness will be highlighted later in the detailed description of an embodiment of the invention.

Preferably, said composition has a pH between 5.0 and 6.0. In order to be stable, i.e., without precipitation of simple or complex salts due to the interaction of the active ingredients or phase separation, the composition according to the invention is preferably formulated at a weakly acidic pH, preferably between 5.0 and 6.0.

Preferably, the three saline or polar active ingredients: sodium hyaluronate, pumpkin seed protein hydrolysate and panthenol, respectively, are incorporated into the formulation object of the invention in the aqueous phase and the apolar hydrocarbon type active ingredient, squalane, is previously incorporated into the fatty phase.

Preferably, said sodium hyaluronate is a hyaluronate corresponding to the high molecular weight fraction between 1.0 and 2.0 mega daltons (MDa), so that it has film-forming capacity that prevents water loss from the skin.

Preferably, the concentration of said sodium hyaluronate is between 0.01% and 0.5% by weight, more preferably between 0.1% and 0.3% by weight, with respect to the total weight of the composition.

Preferably, the concentration of said pumpkin seed protein hydrolyzate is between 1.0% and 8.0% by weight, more preferably between 2.0% and 6.0% by weight, relative to the total weight of the composition.

Preferably, the concentration of said panthenol is between 0.1% and 2.0% by weight, more preferably between 0.2% and 1.0% by weight, relative to the total weight of the composition.

Preferably, the concentration of said squalane is between 0.5% and 5.5% by weight, more preferably between 1.0% and 3.5% by weight, relative to the total weight of the composition.

Preferably, said composition may also comprise other additional emollients, more preferably of the fatty acid glycol ester type, such as butylene glycol dicaprylate/dicaprate or C10-18 triglycerides; and/or also more preferably of the silicone polymer type, such as dimethicone.

Preferably, additional emollients may be used at concentrations between 0.5% and 15.0% by weight, but the ratio of other additional emollients/squalane should not be exceeded 6/1.

Preferably, the water content of said composition is between 55% and 80% by weight, more preferably between 60% and 75% by weight, relative to the total weight of the composition.

Preferably, the concentration of said sodium stearyl lactylate as an anionic emulsifying agent is between 0.1% and 5.0% by weight, more preferably between 0.5% and 2.0% by weight, relative to the total weight of the composition.

Preferably, the concentration of said copolymer of ammonium acryloyldimethyltaurate and vinylpyrrolidone as an anionic thickening agent or rheology modifier is between 0.1% and 2.5% by weight, more preferably between 0.2% and 1.5% by weight, relative to the total weight of the composition.

Preferably, the composition according to the invention comprises, as agents for adjusting the pH, alkaline inorganic hydroxides, more preferably sodium hydroxide or potassium hydroxide, and/or inorganic acids, more preferably hydrochloric acid.

Preferably, the composition according to the invention comprises at least one non-ionic emulsifier.

Preferably, the composition according to the invention comprises other agents such as emulsifying additives, but these will be non-ionic and always in the presence of sodium stearoyl lactylate.

Preferably, said at least one non-ionic emulsifier is selected from the group consisting of glycerol esters of fatty acids or fatty alcohols, more preferably, from glyceryl stearate and cetearyl alcohol.

Preferably, said at least one non-ionic emulsifier is selected from the group consisting of ethoxylated fatty acid esters, more preferably from the group consisting of PEG-23 oleate, PEG-7 stearate, PEG-3 isostearate and PEG-8 C-12-20 fatty acid ester.

Preferably, the concentration of said at least one non-ionic emulsifier is between 0.5% and 5.0% by weight, more preferably between 1.0% and 3.0% by weight, relative to the total weight of the composition.

Preferably, the composition according to the invention has a viscosity between 10,000 cps and 30,000 cps, more preferably between 14,000 cps and 25,000 cps.

Preferably, the composition according to the invention further comprises at least one additional wetting agent, more preferably of the hydroxyl type, and more preferably selected from the group consisting of glycerin and 1,3-propanediol.

Preferably, the concentration of said at least one additional wetting agent is between 1.0% and 15.0% by weight, more preferably between 4.0% and 10.0% by weight, relative to the total weight of the composition.

Preferably, the composition according to the invention further comprises one or more additional components selected from the group consisting of preservatives, antioxidants, chelants, colorants and perfumes.

In one embodiment of the method according to the invention, it comprises between steps a) and b), a step of adjusting the pH of the aqueous phase, with an agent for adjusting the pH, to a value between 4.5 and 6.5, preferably between 5.0 and 6.0.

Preferably, said pH adjusting agent is an alkaline inorganic hydroxide or an inorganic acid. More preferably, said pH adjusting agent is an alkaline hydroxide, even more preferably sodium hydroxide or potassium hydroxide, or hydrochloric acid, respectively.

Preferably, in step b) at least one selected from the group consisting of additional water-soluble wetting agents, water-soluble preservatives, water-soluble chelants and additional water-soluble rheology modifiers, except for the anionic rheology modifier ammonium acryloyldimethyltaurate copolymer and vinylpyrrolidone, is incorporated into the aqueous phase.

Preferably, in step b) said additional water-soluble humectants, and/or said additional water-soluble preservatives, and/or said additional water-soluble chelators and/or said additional water-soluble rheology modifiers, except for the anionic rheology modifier ammonium acryloyldimethyltaurate-vinylpyrrolidone copolymer, are incorporated into the aqueous phase at between 1,350 rpm and 1,450 rpm, maintaining the temperature between 75 °C and 85 °C. After which, the vacuum must be connected to the reactor.

Preferably, in step c) at least one selected from the group consisting of additional non-polar or water-insoluble emollients, non-polar or water-insoluble preservatives and non-polar or water-insoluble antioxidants are incorporated into the fatty phase.

In a preferred embodiment of the invention, step c) comprises the independent preparation of the fatty phase in which said anionic emulsifying agent sodium stearoyl lactylate and said additional non-ionic emulsifiers are incorporated, in addition to more preferably said additional non-polar or water-insoluble emollients, said non-polar or water-insoluble preservatives and/or said non-polar or water-insoluble antioxidants.

Preferably, said first aqueous phase has a water content of between 60% and 75% by weight relative to the total weight of the composition.

Preferably, step a) is carried out at a temperature between 75 °C and 85 °C.

Preferably, step c) is carried out at a temperature between 75 °C and 85 °C.

In a preferred embodiment of the invention, in step d) the anionic rheological modifier copolymer of ammonium acryloyldimethyltaurate and vinylpyrrolidone is added lastly to the fatty phase, maintaining the temperature between 75 °C and 85 °C.

Preferably, in step e) the emulsification is carried out by incorporating the fatty phase into the aqueous phase at a temperature between 75 °C and 85 °C.

Preferably, in step e) the emulsification is carried out by stirring at between 1,550 rpm and 1,650 rpm.

Preferably, step e) consists of emulsifying, at between 1,550 rpm and 1,650 rpm and maintaining the temperature between 75 °C and 85 °C, both the aqueous phase and the fatty phase, adding said fatty phase to said first aqueous phase.

Preferably, step f) is carried out at a temperature between 25 °C and 35 °C.

Preferably, in step f) the emulsion is allowed to cool and when the emulsion reaches between 25 °C and 35 °C, if necessary, the pH is readjusted to a value between 4.5 and 6.5, preferably between 5.0 and 6.0, with the corresponding alkaline hydroxide or hydrochloric acid.

Furthermore, the invention also covers other detailed features illustrated in the detailed description of some embodiments of the invention and in the accompanying figures.

Brief description of the drawings

Other advantages and features of the invention are apparent from the following description, which, without limitation, describes some preferred embodiments of the invention, with reference to the accompanying drawings. The figures show:

Figure 1 - Results obtained during the physicochemical characterization of the emulsion of Example 2.

Figure 2 - Distribution of cases according to the intensity of symptoms assessed by physicians on a Likert-type scale (very severe = 4, severe = 3, moderate = 2, mild = 1, absent = 0).

Figure 3 - Distribution of cases according to the intensity of symptoms assessed by physicians on a Likert-type scale (very severe = 4, severe = 3, moderate = 2, mild = 1, absent = 0), expressed as % of patients who presented the symptom at the baseline visit.

Figure 4 - Evolution of symptom intensity as assessed by physicians. Expressed as number of cases and percentage of the total with symptoms.

Figure 5 - Evolution of symptom intensity after treatment with GV-373 for 30 days. Expressed as a percentage of the total number of cases presenting the symptom (see Figure 4 for more detail). For each symptom, the columns indicate, from left to right, "remission-improvement," "no change," and "worsening."

Figures 6A and 6B - Overall physician (6A) and patient (6B) judgments of GV-373 treatment. Expressed as a % of total cases that responded. For each efficacy category, the columns indicate "good," "fair," and "poor," from left to right.

Figure 7 - Patient evaluation of the GV-373 cosmetology product. Expressed as a percentage of the total number of cases that responded. For each evaluation category, the columns indicate, from left to right, "good," "fair," and "poor."

Detailed description of some embodiments of the invention

Examples

The emulsions of examples 1 and 2 have been prepared by the process described. In the context of the invention, "w/w" refers to weight relative to the total weight of the composition.

Example 1:

Example 2:

STABILITY REPORT

Results

Organoleptic characteristics

Physicochemical characteristics

The physicochemical characterization of the emulsion of example 2 is shown in figure 1.

CLINICAL STUDY

Reference: V.1-10.07.2020

CLINICAL STUDY OF THE ACCEPTABILITY, TOLERABILITY AND EFFICACY OF GV-373 CREAM ON ATROPHIC, SENILE, DRY AND FRAGILE SKIN.

Product: Laboratorios Viñas GV-373 (emulsion from example 2)

1 Title

Clinical study of the acceptability, tolerability and efficacy of GV-373 cream on atrophic, senile, dry and fragile skin.

2 OBJECTIVES AND METHODS

The primary objective of the study was to assess the acceptability, tolerability, and efficacy of GV-373 cream on atrophic, senile, dry, and fragile skin after 30 days of daily treatment.

The study had a phase III, open-label, multicenter, prospective design. Patients were recruited from national dermatology centers.

2.1 Treatment under study

Proposed instructions for use:

• Apply once a day to the affected areas of the body.

• Massage very gently until completely absorbed.

• Do not apply to open wounds.

Study treatment duration: 30 days. Each participant is given two 75 mL samples (150 mL total) to cover the study treatment period.

2.2 Selection criteria

Inclusion criteria

• Patients of either sex.

• Adults.

• Atrophic, senile, dry, fragile skin.

Exclusion criteria:

• Receiving any topical or systemic treatment that could interfere with assessments. • Severe atrophy, with severely compromised skin integrity.

2.3 Main variable

The primary outcome measure was the severity of symptoms of skin aging and fragility (atrophy (thickness), wrinkling, fragility, dryness, pruritus, wounds, and purpura) between the baseline and final visits. This was measured on a qualitative scale of none, mild, moderate, severe, or very severe.

2.4 Secondary variables: safety, adherence, global judgments

For the security variable the following was studied:

- Frequency and characteristics of adverse events.

- Relationship with medication (remote, possible, probable, very probable, not applicable).

For treatment adherence, it was recorded by direct questioning to the patient.

The overall judgments of dermatologists and patients regarding trophic efficacy, moisturizing efficacy, resistance, overall efficacy, tolerability, and acceptability of the treatment were recorded.

In addition, patients were asked about their cosmetological assessment of GV-373, specifically ease of application, spreadability, absorption, odor, and texture.

2.5 Visits made

Each patient underwent a total of two follow-ups: baseline (V1) and final (V2), after 30 days of treatment. The data collection form used is attached in Appendix 1.

3 RESULTS

3.1 Patient profile

included a total of 71 cases with a median age of 74 years [IQR: 64–82 years]. These indicated that the median age at first symptom onset was 65 years [IQR: 57–70 years]. All patients completed treatment.

Table 1 lists the affected areas, which were primarily the lower and upper extremities. Other locations were the neckline (9%, 13 cases), face (1%, 2 cases), forearms (1%, 2 cases), and flanks (1%, 1 case).

29% had only one affected area, 45% had two, 16% had three, 4% had four, and 6% had up to five affected areas. Patients were asked if there were lesions in the affected areas. 77% of patients (N=55) did have lesions, 21% did not, and one case (1%) did not answer. These lesions occurred mainly on the arms (33%; N=39), legs (26%; N=31), hands (19%; N=22), neck (10%; N=12), and other areas (11%; N=13). Of the 13 cases with lesions in other locations, nine were on the décolleté, three on the forearms, three on the face, and one on the temple. Nineteen cases had long-standing lesions (years).

3.2 Assessment of the efficacy of GV-373

Symptom intensity was measured at the baseline and final visits (Figures 2 and 3). At baseline, 96% of patients had atrophy, 83% had wrinkles, 86% had skin fragility, and 100% had dryness. A smaller percentage of patients had pruritus (61%), wounds (25%), and purpura (51%). These symptoms ranged in intensity from mild to severe for atrophy, wrinkles, fragility, and dryness, according to the scale used to measure symptoms, and were mild for pruritus, wounds, and purpura. All symptoms improved after treatment with GV-373, with average symptom intensity ranging from absent to moderate. The Wilcoxon signed-rank test confirmed this improvement (p<0.001 for all symptoms).

The evolution of symptoms, calculated from the baseline and final intensities of each case, is summarized in Figure 4 and Figure 5.

After 30 days of treatment, improvement or remission was observed in 87% of cases for dryness, 82% for pruritus, 89% for wounds, 69% for fragility, 58% for purpura, 55% for wrinkles, and 49% for atrophy. In 6 cases, symptoms worsened or appeared: One case showed the appearance of fragility and mild pruritus, and worsening of dryness (mild to moderate); one case showed the appearance of mild wrinkles; one case showed worsening of wrinkles (moderate to severe) and pruritus (mild to moderate); one case showed worsening of wrinkles (moderate to severe); one case showed the appearance of moderate wrinkles and worsening of atrophy (mild to moderate); and one case reported worsening of atrophy (mild to moderate).

.3 Safety assessment. Adverse reactions.

Safety was excellent; no adverse events were reported (N=70), and one case did not respond to the question. Overall tolerability assessments of GV-373 were rated as "good" by physicians in 90% of cases and by 86% of patients (p-value Chi-1 = 0.726). There were no "poor" assessments.

3.4 Treatment satisfaction. Overall judgments.

In general, the judgments of physicians and patients were very similar (Figures 6A and 6B), with no statistical differences between them (Chi-square test).

The only difference detected was in trophic efficacy, which almost reached statistical significance (p-value Chi = 0.053), indicating that patients had a better perception of the trophic efficacy of the treatment (74%, N = 40) than doctors (58%, N = 32). Even so, the results are good, considering the treatment duration of only 30 days. Longer periods would be necessary to investigate whether this improvement increases or is maintained. Seventy-nine percent (N = 56) of patients responded that they would continue treatment; only two patients indicated that they would not (one of them because they did not like the smell or texture of the preparation, the other did not give a reason). The remaining 18% (N = 13) did not answer the question.

3.5 Acceptability and cosmetogalenics of GV-373

The acceptability of the preparation was rated as "good" by physicians in 92% of cases and by 85% of patients (p-value Chi=0.370). There were no "poor" ratings.

Patients also expressed their opinion on the cosmetogalenic of GV-373 (Figure 7), which was generally excellent.

4 CONCLUSIONS

- 71 patients with atrophic, senile, dry and fragile skin participated, with a median age of 74 years [IQR: 64-82 years], and onset of the first symptoms at 65 years [IQR: 57-70 years].

- At the start of the study, 96% of patients had atrophy, 83% had wrinkles, 86% had skin fragility, and 100% had dryness. A smaller percentage of patients had pruritus (61%), wounds (25%), and purpura (51%).

- After just 30 days of treatment, improvement or remission was observed in 87% of cases for dryness, 82% for pruritus, 89% for wounds, 69% for fragility, 58% for purpura, 55% for wrinkles, and 49% for atrophy.

- The results demonstrate good efficacy, especially in moisturizing, but also in improving resistance and atrophy.

- The safety of GV-373 was excellent, with no adverse events reported, and the tolerability and acceptability of the preparation were highly rated by both dermatologists and patients.

- Of the total number of patients who answered the question, 97% indicated that they would continue with the treatment.

Claims (27)

1. - Cosmetic or pharmaceutical composition in the form of an oil-in-water emulsion, with an aqueous phase and a fatty phase, for topical use, characterized in that it comprises - sodium hyaluronate, - pumpkin seed protein hydrolysate, - panthenol, - squalane, - sodium stearyl lactylate and - copolymer of ammonium acryloyldimethyltaurate and vinylpyrrolidone, and because it has a pH between 4.5 and 6.5. 2. - Composition according to claim 1, characterized in that it has a pH between 5.0 and 6.0. 3. - Composition according to any one of claims 1 and 2, characterized in that said sodium hyaluronate is a hyaluronate corresponding to the high molecular weight fraction comprised between 1.0 and 2.0 MDa, and in that the concentration of said sodium hyaluronate is comprised between 0.01% and 0.5% by weight, preferably between 0.1% and 0.3% by weight, relative to the total weight of the composition. 4. - Composition according to any one of claims 1 to 3, characterized in that the concentration of said pumpkin seed protein hydrolyzate is between 1.0% and 8.0% by weight, preferably between 2.0% and 6.0% by weight, relative to the total weight of the composition. 5. - Composition according to any one of claims 1 to 4, characterized in that the concentration of said panthenol is between 0.1% and 2.0% by weight, preferably between 0.2% and 1.0% by weight, relative to the total weight of the composition. 6. - Composition according to any one of claims 1 to 5, characterized in that the concentration of said squalane is between 0.5% and 5.5% by weight, preferably between 1.0% and 3.5% by weight, relative to the total weight of the composition. 7. - Composition according to any one of claims 1 to 6, characterized in that the water content of said composition is between 55% and 80% by weight, preferably between 60% and 75% by weight, relative to the total weight of the composition. 8. - Composition according to any one of claims 1 to 7, characterized in that the concentration of said sodium stearyl lactylate is between 0.1% and 5.0% by weight, preferably between 0.5% and 2.0% by weight, relative to the total weight of the composition. 9. - Composition according to any one of claims 1 to 8, characterized in that the concentration of said copolymer of ammonium acryloyldimethyltaurate and vinylpyrrolidone is between 0.1% and 2.5% by weight, preferably between 0.2% and 1.5% by weight, relative to the total weight of the composition. 10. - Composition according to any one of claims 1 to 9, characterized in that it comprises, as agents for adjusting the pH, alkaline inorganic hydroxides, preferably sodium hydroxide or potassium hydroxide, and/or inorganic acids, preferably hydrochloric acid. 11. - Composition according to any one of claims 1 to 10, characterized in that it also comprises at least one non-ionic emulsifier. 12. - Composition according to any of claims 1 to 11, characterized in that said composition has a viscosity between 10,000 cps and 30,000 cps, preferably between 14,000 cps and 25,000 cps. 13. - Composition according to any one of claims 1 to 12, characterized in that it also comprises at least one additional wetting agent, preferably of the hydroxyl type, and more preferably glycerin and/or 1,3-propanediol. 14. - Composition according to claim 13, characterized in that the concentration of said at least one additional wetting agent is between 1.0% and 15.0% by weight, preferably between 4.0% and 10.0% by weight, relative to the total weight of the composition. 15. - Composition according to any one of claims 1 to 14, characterized in that it also comprises one or more additional components selected from the group consisting of preservatives, antioxidants, chelants, colorants and perfumes. 16. - Method for preparing a composition according to any one of claims 1 to 15, characterized in that it comprises the following steps: a) preparing a first aqueous phase comprising said sodium hyaluronate and said pumpkin seed protein hydrolysate; b) incorporating into said first aqueous phase said panthenol, preferably dissolved in water; c) preparing a fatty phase comprising said sodium stearoyl lactylate and said squalane; d) lastly adding said copolymer of ammonium acryloyldimethyltaurate and vinylpyrrolidone to the fatty phase; e) emulsifying said first aqueous phase and said fatty phase by adding said fatty phase to said first aqueous phase, obtaining an emulsion; f) if necessary, adjust the pH, using a pH adjusting agent, to a value between 4.5 and 6.5, preferably between 5.0 and 6.0. 17. - Method according to claim 16, characterized in that it comprises, between steps a) and b), a step of adjusting the pH of the aqueous phase, with an agent for adjusting the pH, to a value between 4.5 and 6.5, preferably between 5.0 and 6.0. 18. - Method according to any of claims 16 or 17, characterized in that said agent for adjusting the pH is an alkaline inorganic hydroxide and/or an inorganic acid, said agent for adjusting the pH preferably being sodium hydroxide, potassium hydroxide, and/or hydrochloric acid. 19. - Method according to any one of claims 16 to 18, characterized in that at least one selected from the group consisting of additional water-soluble wetting agents, water-soluble preservatives, water-soluble chelants and additional water-soluble rheological modifiers is incorporated into the aqueous phase. 20. - Method according to any one of claims 16 to 19, characterized in that at least one selected from the group consisting of additional non-polar or water-insoluble emollients, non-polar or water-insoluble preservatives and non-polar or water-insoluble antioxidants is incorporated into the fatty phase. 21. - Method according to any one of claims 16 to 20, characterized in that said first aqueous phase has a water content of between 60% and 75% by weight with respect to the total weight of the composition. 22.- Method according to any one of claims 16 to 21, characterized in that step a) is carried out at a temperature between 75 °C and 85 °C. 23. - Method according to any one of claims 16 to 22, characterized in that step c) is carried out at a temperature between 75 °C and 85 °C. 24. - Method according to any one of claims 16 to 23, characterized in that in step e) the emulsification is carried out by incorporating the fatty phase into the aqueous phase at a temperature between 75 °C and 85 °C. 25.- Method according to any one of claims 16 to 24, characterized in that in step e) the emulsification is carried out by stirring at between 1,550 rpm and 1,650 rpm. 26. - Method according to any one of claims 16 to 25, characterized in that step f) is carried out at a temperature between 25 °C and 35 °C. 27. - Composition according to any one of claims 1 to 15 for use in the treatment of senile skin.