Oil-in-water emulsions for topical administration and uses thereof

Abstract

an oil phase comprising a first therapeutic agent; aqueous phase, 1. An oil-in-water Pickering emulsion comprising polyester nanoparticles containing a second therapeutic agent, the oil phase is in the form of droplets dispersed in an aqueous continuous phase; at least a portion of the nanoparticles are localized at the interface between the oil phase and the aqueous phase; 1. An oil-in-water Pickering emulsion, characterized in that the aqueous phase contains hyaluronic acid. This new emulsion allows the topical treatment of inflammatory skin diseases such as psoriasis, atopic dermatitis, or prurigo, benign dermatitis such as inflammatory acne, scalp diseases such as alopecia, cosmetic skin conditions such as very dry and sensitive skin, neoplastic pathologies such as mycosis fungoides (low-grade cutaneous T-cell lymphoma) or cutaneous mastocytosis (accumulation and abnormal proliferation of mast cells in the dermis, accompanied by intense pruritus), and fibrotic pathologies such as keloids (raised, pruritic, dystrophic scars that do not regress spontaneously and can extend beyond the site of trauma / injury).

Description

[Technical Field]

[0001] The present disclosure relates to therapeutic oil-in-water emulsions for topical administration, more particularly Pickering emulsions co-encapsulating at least two therapeutic agents, and their use for the treatment of skin pathologies, such as inflammatory skin diseases. [Background technology]

[0002] Local application of drugs to the site of pathology offers the advantage of delivering the drug directly to the site of action, generating high tissue concentrations of the drug, and avoiding undesirable side effects of other routes of administration, such as administration to the stomach in the case of oral delivery of nonsteroidal anti-inflammatory drugs.

[0003] Emulsions can be used for topical drug administration. Emulsions can encapsulate one or more therapeutic agents (in the oil and / or aqueous phase), offering potential advantages, such as protecting the drug from degradation, maintaining its activity, improving the drug's transdermal permeability, or controlling and sustaining the drug's release. However, because emulsions are thermodynamically unstable, they are widely stabilized by synthetic surfactants, which directly or indirectly cause toxicity and environmental problems. During long-term topical treatment, skin irritation is often observed due to the surfactants' disruption of the skin's barrier function.

[0004] A new approach to emulsion stabilization is the use of solid particles to stabilize the oil-water interface. Such emulsions, called Pickering emulsions, were described by Pickering and Ramsden over a century ago. They exhibit long-term stability due to the solid particles forming a physical barrier against destabilizing phenomena, such as coalescence.

[0005] However, such emulsions have a tendency to cream over time, ie, the dispersed phase tends to migrate to the surface of the emulsion, thereby creating inhomogeneity within the emulsion. Summary of the Invention [Problem to be solved by the invention]

[0006] The present disclosure provides novel therapeutic oil-in-water emulsions that are stable over time, particularly for at least 24 hours.

[0007] The present disclosure provides novel stable oil-in-water emulsions with immunomodulatory and anti-inflammatory properties.

[0008] The present disclosure provides novel stable oil-in-water emulsions that contain at least one anti-inflammatory agent and have multipurpose efficacy superior to conventional treatments.

[0009] The present disclosure provides novel oil-in-water emulsions that can be loaded with different therapeutic agents, can be used for topical application, and have potential cosmetic virtues.

[0010] The present disclosure provides novel oil-in-water emulsions that are biodegradable, biocompatible, and potentially improve user compliance due to the amalgamation of multiple active agents in a single emulsion.

[0011] The present disclosure provides novel oil-in-water emulsions that have a very good texture, i.e., not too liquid, not too thick, allowing for comfortable application of the treatment for the patient, and the texture is reproducible.

[0012] The present disclosure provides novel oil-in-water emulsions that allow active ingredients to penetrate the skin properly for effective application.

[0013] The present disclosure provides novel oil-in-water emulsions that ensure good hydration of the skin after application, an essential condition for successful treatment of inflammatory skin diseases such as psoriasis, especially for mature skin. [Means for solving the problem]

[0014] Therefore, the present disclosure provides: an oil phase comprising a first therapeutic agent; aqueous phase, 1. An oil-in-water Pickering emulsion comprising polyester nanoparticles containing a second therapeutic agent, the oil phase is in the form of droplets dispersed in an aqueous continuous phase; at least a portion of the nanoparticles are localized at the interface between the oil phase and the aqueous phase; The present invention relates to an oil-in-water Pickering emulsion, characterized in that the aqueous phase contains hyaluronic acid. [Brief explanation of the drawings]

[0015] [Figure 1] Figure 1 shows the emulsion on day 1. [Figure 2] Figure 2 shows the continuous changes from day 1 to day 28 in the HA-free emulsion layer and the aqueous phase below the emulsion layer. [Figure 3] Figure 3 shows that the emulsion layer occupies nearly the entire sample and remains stable for 28 days due to the presence of HA in the outer aqueous phase. [Figure 4] FIG. 4 shows the change in viscosity as a function of shear rate for a white emulsion containing HA in the external phase (i.e., without any active substance). [Figure 5] FIG. 5 shows the results expressed as the mean±SEM of the PASI score from each group of 12 mice. [Figure 6] Figure 6 shows the effect of adding hyaluronic acid (HA) at a molar mass of 1.5 MDa to the external phase of the emulsion compared to Carbopol emulsion in vivo in a mouse model of imiquimod-induced psoriasis. DETAILED DESCRIPTION OF THE INVENTION

[0016] Hyaluronic acid, as used herein, refers to all physiological forms of hyaluronic acid, the most common being the sodium salt.

[0017] In the emulsions disclosed herein, the pH of the emulsion is 4.5 to 6.5, particularly 5 to 6.

[0018] The pH of the emulsion is measured by simply placing a pH electrode in the emulsion.

[0019] In this range, the hyaluronic acid is primarily in its ionized form (e.g., as sodium hyaluronate) and therefore most efficiently provides its thickening effect. Furthermore, since the natural pH of skin is about 5.5, this pH range is particularly suited for topical application of the emulsion to the skin.

[0020] In the emulsions disclosed herein, one role of the nanoparticles is to stabilize the emulsion by preventing or delaying oil droplet coalescence and / or Ostwald ripening. In the emulsions disclosed herein, the nanoparticles make it possible to avoid the use of surfactants to stabilize the emulsion. Thus, the emulsions disclosed herein may be surfactant-free, which is advantageous for pharmaceutical and cosmetic applications.

[0021] Such emulsions stabilized by nanoparticles located at the interface between the oil and aqueous phases are called Pickering emulsions.

[0022] Hydrophilic nanoparticles favor the formulation of O / W Pickering emulsions (rather than W / O emulsions). Furthermore, if there is a surplus of nanoparticles that are not adsorbed at the interface between the oil and aqueous phases, this surplus will be found primarily in the aqueous phase.

[0023] In the emulsion disclosed herein, hyaluronic acid acts as a thickener to stabilize emulsion by delaying the creaming and / or coalescence and ripening process of emulsion.Although it is known to add thickener to stabilize emulsion, it is still difficult to predict how thickener will affect the interfacial properties of emulsion, especially when the emulsion is a Pickering emulsion.For example, if thickener tends to adsorb to particles or oil-water interface, it may destabilize emulsion.

[0024] Hyaluronic acid also has moisturizing, soothing and anti-aging properties.

[0025] Here, hyaluronic acid was found to be effective in stabilizing emulsions without adversely affecting the properties of the emulsions. Furthermore, in vivo studies have shown that the emulsions disclosed herein stabilized with hyaluronic acid have high potential in the treatment of skin disorders.

[0026] In the emulsions disclosed herein, the oil phase may comprise at least one oil selected from fatty acids, fatty acid esters, vegetable oils, mineral oils, and mixtures thereof.

[0027] As defined herein, oils are non-aqueous, non-polar chemicals that contain primarily hydrocarbons. They are both hydrophobic (not easily mixed with water) and lipophilic (easy to mix with other oils). They are liquid at 25°C and 1.013 bar.

[0028] In the emulsions disclosed herein, the vegetable oil may be selected from castor oil, sesame oil, poppy seed oil, soybean oil, olive oil, walnut oil, palm oil, and mixtures thereof.

[0029] Other vegetable oils suitable for use in the emulsions disclosed herein include safflower oil and palm kernel oil.

[0030] Fatty acid esters suitable for use in the emulsions disclosed herein include triglycerides, particularly triglycerides of long chain fatty acids (TLCFAs) and / or triglycerides of medium chain fatty acids (TMCFAs).

[0031] One example of a TLCFA suitable for use in the emulsions disclosed herein is triolein.

[0032] Examples of TMCFAs suitable for use in the emulsions disclosed herein include triglycerides of caprylic and / or capric acid. Suitable TMCFAs for use in the emulsions disclosed herein include MIGLYOL 810® or 812 N®, NEOBEE® M-5, Captex® 300, and Labrafac® lipophile WL 1349.

[0033] Other triglycerides suitable for use in the emulsions disclosed herein include the triglyceride of caprylic, capric and linoleic acid (MIGLYOL 818®) and the triglyceride of caprylic, capric and succinic acid (MIGLYOL 829®).

[0034] Other fatty acid esters suitable for use in the emulsions disclosed herein include propylene glycol dicaprylate / dicaprate (MIGLYOL 840®), propylene glycol dicaprylate / dicaprate (Labrafac® PG), and glyceryl oleate (Peceol®).

[0035] In the emulsions disclosed herein, the fatty acid esters may be selected from triglycerides of medium chain fatty acids, particularly medium chain fatty acids that may contain from 8 to 12 carbon atoms.

[0036] The emulsions disclosed herein may comprise from 5% to 70% by weight of the oil phase, based on the total weight of the emulsion.

[0037] In the emulsions disclosed herein, the droplets forming the oil phase may have a size of at least 1 μm.

[0038] In the emulsions disclosed herein, the droplets forming the oil phase may have a size distribution ranging from 1 μm to 100 μm as measured by dynamic light scattering.

[0039] Polyester nanoparticles have low toxicity and cause limited inflammatory responses.

[0040] Additionally, in the emulsions disclosed herein, the polyester nanoparticles may be biodegradable.

[0041] Thus, the emulsions disclosed herein may be more biocompatible, biodegradable, and less toxic or irritating than emulsions stabilized with surfactants or mineral particles.

[0042] In the emulsions disclosed herein, the polyester nanoparticles may be solid nanoparticles (i.e., without internal cavities). In particular, they may have at least two dimensions less than 1 μm. In particular, the polyester nanoparticles may be spherical solid nanoparticles having a diameter of less than 1 μm, particularly 20 nm to 400 nm, as measured by dynamic light scattering.

[0043] In this case, the diameter is the z-average, ie, the intensity-weighted average hydrodynamic size of the ensemble collection of particles as measured by dynamic light scattering (DLS).

[0044] The concentration of nanoparticles in the emulsions disclosed herein may be from 5 mg / mL to 40 mg / mL of emulsion.

[0045] In the emulsions disclosed herein, the polyester may be selected from polylactic acid, polyglycolic acid, copolymers of lactic acid and glycolic acid, copolymers of lactic acid, glycolic acid and ethylene glycol, polyorthoesters, polyanhydrides, polylactones such as polybutyrolactone or polyvalerolactone, polymalic acid, and mixtures thereof.

[0046] In particular, when the polyester is poly(lactic-co-glycolic acid), the poly(lactic-co-glycolic acid) may have a lactic acid / glycolic acid ratio of 1-6, preferably 2-4.

[0047] In the emulsions disclosed herein, the polyester may be poly(lactic-co-glycolic acid) having a lactic acid / glycolic acid ratio of 2 to 4 and an intrinsic viscosity of 0.25 dL / g to 0.5 dL / g measured at 25°C at a concentration of 0.1% by weight in CHCl3.

[0048] In the emulsions disclosed herein, the first therapeutic agent may be selected from anti-inflammatory agents, such as calcitriol, calcipotriol, maxacalcitol, curcumin, glucocorticoids, particularly betamethasone or dexamethasone, and natural or semi-synthetic analogs derived from metabolites of vitamin E.

[0049] In the emulsions disclosed herein, the second therapeutic agent may be selected from immunosuppressants such as calcineurin inhibitors, particularly tacrolimus and cyclosporin A, or JAK / STAT inhibitors, particularly immunosuppressants such as tofacitinib, e.g., tofacitinib citrate, baricitinib, e.g., baricitinib phosphate, and ruxolitinib, or steroid inhibitors, particularly immunosuppressants such as cucurbitacin B hydrate, or STAT inhibitors, particularly STAT (CAS number: 19983-44-9).

[0050] In the emulsions disclosed herein, the oil phase may further comprise an antioxidant, such as vitamin E, vitamin C, resveratrol or N-acetylcysteine, especially vitamin E.

[0051] In the emulsions disclosed herein, the hyaluronic acid may have a molar mass of 5,000 g / mol to 5,000,000 g / mol, in particular 100,000 g / mol to 3,000,000 g / mol, more in particular 500,000 g / mol to 2,500,000 g / mol, and even more in particular 1,000,000 g / mol to 2,500,000 g / mol.

[0052] In the emulsions disclosed herein, the concentration of the hyaluronic acid in the aqueous phase, calculated as the mass of the hyaluronic acid in grams contained in 100 mL of aqueous phase, may be 0.15% to 5%, for example, 0.2% to 2% or 0.5% to 5%, particularly 0.25% to 1.5% or 1% to 3%.

[0053] The above concentrations of hyaluronic acid make it possible to obtain a stable emulsion of satisfactory viscosity.

[0054] The emulsion disclosed herein may comprise tacrolimus as a first therapeutic agent and calcitriol as a second therapeutic agent. This embodiment of the emulsion disclosed herein has achieved particularly good results. Specifically, in this case, surprisingly, in vivo studies have shown that the emulsion disclosed herein is more effective than a comparable emulsion in which hyaluronic acid is replaced with Carbopol as a thickening agent.

[0055] Carbopol, also known as carbomer, is a high molar mass synthetic biocompatible polymer composed of repeating acrylic acid units. In Carbopol, the polymer chains are crosslinked with allyl sucrose or other allyl esters. Typically, more than 50% of the monomer units in Carbopol contain carboxylic acid groups.

[0056] The advantages of encapsulating a second therapeutic agent in nanoparticles include enhanced skin permeability, creation of a therapeutic agent reservoir within the hair follicle, protection of the encapsulated therapeutic agent, and gradual release of the therapeutic agent.

[0057] The advantage of the oil phase is the protection and gradual release of the therapeutic agent. Indeed, encapsulation in the oil phase is advantageous in that it allows the protection and therefore stabilization of certain therapeutic agents, especially fragile molecules. The presence of nanoparticles at the interface of the external aqueous phase and the internal oil phase enhances emulsion stability and the protection of the therapeutic agent.

[0058] The advantages of combining two therapeutic agents and hyaluronic acid distributed across the three phases of an emulsion (aqueous phase, oil phase, and nanoparticles) include gradual and variable release kinetics of the therapeutic agents and hyaluronic acid, providing greater efficacy than each of the therapeutic agents and hyaluronic acid used separately, and resulting in better compliance with the combined treatment compared to the three separate applications.

[0059] According to another aspect, the present disclosure also relates to a pharmaceutical composition comprising an emulsion disclosed herein and at least one pharmaceutically acceptable excipient.

[0060] These pharmaceutical compositions comprise an effective amount of at least one emulsion disclosed herein, as well as at least one pharmaceutically acceptable excipient.

[0061] The excipients are selected, depending on the pharmaceutical form and the desired mode of administration, from the usual excipients known to those skilled in the art.

[0062] The mode of administration can be topical application to the area of ​​damaged skin, subcutaneous injection, or intradermal injection.

[0063] According to normal practice, the appropriate dosage for each patient will be determined by the physician based on the mode of administration, the body weight and the patient's response.

[0064] According to another aspect, the present disclosure relates to an emulsion as disclosed herein for use in a method for the treatment of the human or animal body, particularly skin pathologies.

[0065] According to another aspect, the present disclosure relates to a therapeutic method for treating a skin pathology comprising administering to a patient an effective amount of the emulsion disclosed herein.

[0066] According to the present disclosure, skin pathologies may include: Inflammatory skin diseases, such as psoriasis, atopic dermatitis, or prurigo, Benign dermatitis, such as inflammatory acne, Cosmetic skin conditions, e.g. very dry, sensitive and prurigo-prone skin, scalp diseases, e.g. alopecia areata, lichen planus, various alopecia including... Cutaneous mastocytosis (accumulation and abnormal proliferation of mast cells in the dermis, accompanied by severe itching, fibrotic pathologies, such as keloids (raised, itchy, dystrophic scars that do not regress spontaneously and have the property of being able to extend beyond the site of trauma / injury); Neoplastic pathologies such as mycosis fungoides (low-grade cutaneous T-cell lymphoma) or basal carcinoma. [Example]

[0067] chemicals Poly(lactic acid-coglycosidic) acid (PLGA, 75:25 Resomer® RG753 H with acid end groups (intrinsic viscosity: 0.32-0.44 dL / g)) was purchased from Evonik (Germany).

[0068] Miglyol 812 N was purchased from Cremer Oleo GmbH & Co (Germany).

[0069] Tacrolimus monohydrate (TAC) and cyclosporine A (CysA) were purchased from INRESA (France).

[0070] Calcitriol (CAL) was purchased from Bertin Pharma (France).

[0071] α-Tocopherol (Vit E) (purity ≥96%), calcein, and phosphate were purchased from Sigma-Aldrich (France).

[0072] Carbopol 974P was purchased from Lubrizol (France).

[0073] Hyaluronic acid (molar mass 1550000 g / mol) was purchased from ACROS organics.

[0074] Preparation of nanoparticles (NPs) PLGA nanoparticles were prepared by emulsion evaporation or nanoprecipitation (see C.E. Astete, C.M. Sabliov, Synthesis and Characterization of PLGA Nanoparticles, J. Biomater. Sci. Polym. Ed. 17 (2006) 247-289 and C. Albert, N. Huang, N. Tsapis, S. Geiger, V. Rosilio, G. Mekhloufi, D. Chapron, B. Robin, M. Beladjine, V. Nicolas, E. Fattal, F. Agnely, Bare and Sterically Stabilized PLGA Nanoparticles for the Stabilization of Pickering Emulsions, Langmuir. 34 (2018) 13935-13945).

[0075] In the emulsification-evaporation process, PLGA was dissolved in a dichloromethane / acetone mixture, and an aqueous PVA (polyvinyl alcohol) solution was emulsified by sonication. After evaporating the organic solvent at room temperature, the NPs were purified by ultracentrifugation. After removing the supernatant, the nanoparticles were resuspended in an aqueous solution containing trehalose (a cryoprotectant). The NP suspension was then freeze-dried. Before use, the freeze-dried NPs were redispersed in MilliQ water to the desired concentration.

[0076] In the nanoprecipitation process, an organic solution of PLGA dissolved in acetonitrile was injected into the PVA solution using a syringe pump. Evaporation of the organic solvent was carried out at room temperature under a hood. The nanoparticles were then purified by ultracentrifugation. After the purification step, the NPs were redispersed in MilliQ water to the desired concentration.

[0077] PLGA nanoparticles with SA were prepared by adding a second therapeutic agent (e.g., cyclosporine A (CysA) or tacrolimus (TAC) or the phosphate salt of tofacitinib citrate (Tofa) or baricitinib (Bari) or ruxolitinib (Ruxo)) to the PLGA / organic solvent mixture at 10% by weight of the polymer.

[0078] The above process gave an encapsulation efficiency (mass of active substance in NPs / total mass of active substances used) of more than 75% and a loading amount (mass of active substance in NPs / total mass of NPs) that was capable of achieving a biological effect (the loading amount was dependent on the active substance).

[0079] Control NPs were prepared following the same method but without any active pharmaceutical ingredient (API).

[0080] Preparation of a stabilized water-in-oil emulsion with a concentration of 25 mg / mL of PLGA nanoparticles and an oil / aqueous phase mass ratio of 20 / 80 To the oil phase, 3 μg of CAL per gram of emulsion and 10 μg of vitamin E per gram of emulsion were added, respectively. To each NP suspension (PLGA, PLGA-CysA, and PLGA TAC), increasingly concentrated solutions of Carbopol or hyaluronic acid were added to obtain aqueous phases with Carbopol concentrations of 0.2% w / vol (i.e., 0.2 g of Carbopol per 100 mL of aqueous phase) or hyaluronic acid concentrations of 1.5% w / vol (i.e., 1.5 g of HA per 100 mL of aqueous phase) in the aqueous suspension. The aqueous and oil phases were mixed at 20,000 rpm for 2 minutes using an Ultra-Turrax (IKA T10) to obtain emulsions. For emulsions containing Carbopol, 15 seconds before the end of emulsification with the Ultra-Turrax, three drops of 0.25 M sodium hydroxide (NaOH) solution were added to the emulsion using a Pasteur pipette to neutralize the thickener and induce gelation.

[0081] Stability of emulsions with and without hyaluronic acid (HA) in the external phase Emulsions were prepared by blending 25 mg / mL aqueous suspensions of PLGA nanoparticles with a 20 / 80 mass ratio of oil phase (Miglyol) to aqueous phase, with or without active substances (TAC or Cys A in the nanoparticles, CAL in the oil phase, or no active substance in the emulsion). Emulsions without any active substance are referred to as white emulsions. The effect of adding HA with a molar mass of 1.5 MDa to the external phase of the emulsions was investigated.

[0082] Photographs of the emulsions were taken to visualize their behavior (Figure 1). The emulsions were also analyzed using a Turbiscan® MA 2000 (Formulaction, Toulouse, France). Measurements were performed at set times by recording the backscattered and / or transmitted light intensity curves. The Turbiscan allows for the measurement of destabilization phenomena in samples without dilution. The rheological behavior of the emulsions was measured using an AR-G2 rheometer (TA instruments, USA) equipped with a planar geometry (40 mm diameter, 100 μm air gap). The temperature was controlled at 20 °C using a Peltier plane.

[0083] Figure 1 shows the emulsions on day 1. Creaming was visible as early as day 1 in the emulsion without HA (left), while the presence of 1.5% by weight HA in the external phase resulted in an emulsion layer spanning almost the entire height of the sample (right).

[0084] The stability of emulsions with and without HA was monitored using Turbiscan (Figures 2 and 3). Figure 2 shows the continuous evolution of the emulsion layer without HA and the aqueous phase below it from day 1 to day 28. A rapid formation of creaming is observed, thinning the aqueous phase over time. In Figure 3, the emulsion layer occupies almost the entire sample and remains stable for 28 days due to the presence of HA in the outer aqueous phase. HA acts as a thickener and stabilizer for the outer aqueous phase.

[0085] The viscosity of emulsions with and without HA in the external phase was investigated and compared to the viscosity of an emulsion containing 0.2% by weight of Carbopol as a thickener in the aqueous external phase. The emulsion with Carbopol had a texture suitable for the desired application, and therefore its viscosity was used as a reference.

[0086] Figure 4 shows the change in viscosity as a function of shear rate for a white emulsion containing HA in the external phase (i.e., without any active agent). The curves are compared with those for a white emulsion without a thickener in the external phase and an emulsion containing 0.2% Carbopol in the external phase.

[0087] We can observe shear thinning behavior of all emulsions (viscosity decreases as shear rate increases). The addition of thickeners, HA or Carbopol, significantly increases the viscosity of the emulsions over the entire range of shear rates investigated. The viscosity of the emulsion containing 1.5% HA in the external phase is comparable to that of the emulsion containing 0.2% Carbopol (or 0.2 s -1 (slightly higher shear rate than ultra).

[0088] It was also possible to obtain stable emulsions at other concentrations of hyaluronic acid in aqueous suspension, including, for example, 0.5%, 1%, or 1.25% w / vol (i.e., 0.5, 1, or 1.25 g of HA per 100 mL of aqueous phase), which can provide stable emulsions with different viscosity profiles.

[0089] In vivo effects of Carbopol emulsion on imiquimod (IMQ)-induced psoriasis model in mice After specifically inducing psoriasis-like skin disease with IMQ in BALB / c mice, the biological effects of the emulsions and the "skin" scores of the emulsions (white control vs. AS emulsion) were examined for 7 days.

[0090] The results are presented in Figure 5 as the mean ± SEM of the PASI score from each group of 12 mice, where the total emulsions containing calcitriol (Ca) and an active immunosuppressant (cyclosporine A or tacrolimus), i.e., (ECiCa) and (ETaCa), were compared with a "white emulsion" (EB: Emulsion "Blanche") without the active substance.

[0091] In vivo effects of HA emulsion on imiquimod (IMQ)-induced psoriasis model in mice The effect of adding hyaluronic acid (HA) at a molar mass of 1.5 MDa to the external phase of the emulsion was compared with Carbopol emulsion in vivo in a mouse model of imiquimod-induced psoriasis (Figure 6).

[0092] The PAS score for mice phenotypically resembling psoriasis was calculated. BALB / c mice were treated daily with IMQ cream or control cream on the shaved dorsal skin and right ear. Erythema, scaling, and thickness of the dorsal skin were scored daily on a scale of 0 to 4. Results were expressed as a cumulative score (erythema + scaling + thickness), depicted and reported here as the PASI total score (vertical axis).

[0093] The present results clearly demonstrate the clinical efficacy of the innovative Pickering emulsion in IMQ-induced psoriasis-like dermatosis.

[0094] No significant differences were observed in vivo in IMQ-induced psoriasis in the presence of "Carbopol-prepared emulsion" compared to "HA-prepared emulsion."

[0095] In the case of ETaCa emulsion, "HA emulsion" appears to have a better effect than "Carbopol-prepared emulsion."

Claims

1. an oil phase comprising a first therapeutic agent; aqueous phase, Polyester nanomolecules containing a second therapeutic agent 1. An oil-in-water Pickering emulsion comprising: the oil phase is in the form of droplets dispersed in an aqueous continuous phase; at least a portion of the nanoparticles are localized at the interface between the oil phase and the aqueous phase; 1. An oil-in-water Pickering emulsion, characterized in that the aqueous phase contains hyaluronic acid.

2. 2. The emulsion according to claim 1, wherein the pH of the emulsion is between 4.5 and 6.5, in particular between 5 and 6.

3. 3. The emulsion of claim 1, wherein the oil phase comprises at least one oil selected from fatty acids, fatty acid esters, vegetable oils, mineral oils, and mixtures thereof.

4. 4. An emulsion according to claim 3, wherein the fatty acid ester is selected from triglycerides of medium chain fatty acids, in particular medium chain fatty acids containing from 8 to 12 carbon atoms.

5. 5. An emulsion according to claim 1, wherein the droplets forming the oil phase have a size distribution in the range of 1 μm to 100 μm as measured by dynamic light scattering.

6. 6. The emulsion according to claim 1, wherein the polyester is selected from polylactic acid, polyglycolic acid, copolymers of lactic acid and glycolic acid, copolymers of lactic acid, glycolic acid and ethylene glycol, polyorthoesters, polyanhydrides, polylactones, such as polybutyrolactone or polyvalerolactone, polymalic acid, and mixtures thereof.

7. 7. The emulsion of claim 6, wherein the polyester is poly(lactic-co-glycolic acid), in particular the poly(lactic-co-glycolic acid) has a lactic acid / glycolic acid ratio between 1 and 6.

8. 8. The emulsion of claim 1, wherein the first therapeutic agent is selected from anti-inflammatory agents, such as calcitriol, calcipotriol, maxacalcitol, curcumin, glucocorticoids, in particular betamethasone or dexamethasone, and natural or semi-synthetic analogs derived from metabolites of vitamin E.

9. 9. The emulsion of claim 1, wherein the second therapeutic agent is selected from immunosuppressants such as calcineurin inhibitors, particularly tacrolimus and cyclosporin A, or JAK / STAT inhibitors, particularly immunosuppressants such as tofacitinib, e.g., tofacitinib citrate, baricitinib, e.g., baricitinib phosphate, and ruxolitinib, or immunosuppressants such as steroid inhibitors, particularly cucurbitacin B hydrate, or STAT inhibitors, particularly STAT (CAS number: 19983-44-9).

10. 10. The emulsion according to claim 1, wherein the oil phase further comprises an antioxidant, such as vitamin E, vitamin C, resveratrol or N-acetylcysteine, in particular vitamin E.

11. 11. The emulsion according to claim 1, wherein the molar mass of the hyaluronic acid is from 5,000 g / mol to 5,000,000 g / mol, in particular from 100,000 g / mol to 3,000,000 g / mol, more particularly from 500,000 g / mol to 2,500,000 g / mol, and even more particularly from 1,000,000 g / mol to 2,500,000 g / mol.

12. 12. The emulsion according to claim 1, wherein the concentration of the hyaluronic acid in the aqueous phase, calculated as the mass of the hyaluronic acid in grams contained in 100 mL of the aqueous phase, is between 0.15% and 5%, such as between 0.2% and 2% or between 0.5% and 5%, in particular between 0.25% and 1.5% or between 1% and 3%.

13. the first therapeutic agent is tacrolimus; 13. The emulsion of any one of claims 1 to 12, wherein the second therapeutic agent is calcitriol.

14. A pharmaceutical composition comprising the emulsion of any one of claims 1 to 13 and at least one pharmaceutically acceptable excipient.

15. 14. An emulsion according to any one of claims 1 to 13 for use in a method for the treatment of the human or animal body, in particular for the treatment of skin pathologies.

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