Hydrogel compositions, and their use in the prevention and / or treatment of skin damage caused by radiation.

Abstract

The present invention relates to a composition suitable for topical administration, which is aqueous and contains a vasoconstrictor.The present invention is characterized in that the composition contains a hydrophilic film-forming agent selected from polyethylene glycol in combination with propylene glycol and / or dimethyl sulfoxide (DMSO); polyvinylpyrrolidone / vinyl acetate copolymer, polyvinylpyrrolidone in uncrosslinked, crosslinked or acetate form, used alone or in combination; a vasoconstrictor selected from brimonidine or its salts in a solvent system phase containing glycerin; and is in the form of a hydrogel.The present invention also relates to a composition for its use as a medicine, more particularly in the prevention and / or treatment of dermatitis caused by radiation, especially in the context of treatment by radiation therapy.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical compositions in a form suitable for topical administration. More particularly, the present invention relates to pharmaceutical compositions containing a vasoconstrictor, such as brimonidine or a salt thereof, and to compositions for use as a medicament, more particularly for the prevention and / or treatment of radiation damage to the skin.

[0002] Types of radiation that can cause skin damage include ultraviolet (UV) rays, including UVA and UVB, which can cause sunburn, visible light rays, infrared radiation (IR), ionizing radiation, such as X-rays and α, β or γ rays, and radiation consisting of protons.

Background Art

[0003] One of the initial effects of radiation exposure to tissue is erythema, an inflammatory response that causes vasodilation and redness of the skin. This reaction is seen approximately 6 - 8 hours after exposure to UV and disappears after 36 - 48 hours.

[0004] The topical application of highly selective α2 - adrenergic receptor agonists to the face is known to reduce erythema by direct cutaneous vasoconstriction. The main feature of cutaneous vasoconstriction is pallor, which results in an immediate reduction in blood flow by reducing the diameter of arterioles and small blood vessels in the dermis, particularly manifested as a reduction in the color of the skin.

[0005] MIRVASO® Gel (0.5% w / w brimonidine tartrate) is indicated for the treatment of facial erythema associated with rosacea in adults. In addition to brimonidine tartrate, this gel contains carbomer homopolymer type B, glycerin, methylparaben, phenoxyethanol, propylene glycol, sodium hydroxide, titanium dioxide and purified water.

[0006] Brimonidine is known as a particularly highly selective α2-adrenergic receptor agonist. Brimonidine exhibits more than 1000 times greater selectivity for α2-adrenergic receptors than for α1-adrenergic receptors.

[0007] Brimonidine has been shown to be useful in treating erythema caused by rosacea and has also been proposed for other skin disorders. See, for example, U.S. Patent Applications 10 / 853585, 10 / 626037, and 12 / 193098.

[0008] U.S. Patent Application Publication No. 2020 / 121675 describes a gel formulation for the treatment of rosacea comprising 0.3% brimonidine, 1% benzyl alcohol, ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, carbomer homopolymer type B, disodium edetate, hexylene glycol, poloxamer 407, polyethylene glycol 400, polysorbate 40, purified water, and tromethamine.

[0009] Topical formulations designed for therapeutic purposes typically consist of an active agent and excipients. During formulation, the selection of excipients is necessary to ensure drug efficacy by solubility of the active agent and optimizing its skin penetration, for the sake of galenos-like stability and texture, local tolerance, and patient compliance. Identifying the optimal balance of these critical factors, as well as optimizing each individual element, to supply products that meet the needs of patients, healthcare professionals, and regulators is a complex and complementary problem.

[0010] Brimonidine (tartrate) exhibits a solubility profile that provides chemical stability suitable for topical administration and offers a variety of formulation options.

[0011] On the other hand, ionizing surfactants containing salts do not easily penetrate the stratum corneum (a barrier mainly composed of lipids), making it difficult to release the surfactant and form a skin reservoir. Furthermore, such surfactants tend to be rapidly removed from biological tissues due to their solubility in water.

[0012] In fact, because brimonidine is a hydrophilic molecule, it does not easily pass through the lipid-rich stratum corneum.

[0013] However, once brimonidine crosses the stratum corneum, it enters the hydrophilic media (epidermis, especially the granular and basal layers, and then the dermis) and is subsequently eliminated, thus reducing its effectiveness in terms of vasoconstriction.

[0014] Therefore, the barrier structure formed by the skin presents a real challenge in obtaining topical formulations designed for skin application that can exert a rapid, consistent, and long-lasting vasoconstrictive effect for 16 or even 24 hours, without the active vasoconstrictor being immediately eliminated in the lower hydrophilic layer after passing through the outer lipid layer.

[0015] Furthermore, the concentration of active vasoconstrictors should not be too high, as this poses a significant and potentially harmful risk of systemic exposure.

[0016] Furthermore, certain compounds used in compositions for topical application may cause side effects, potentially limiting their use and effectiveness. For example, certain active ingredients have the significant drawback of causing irritation, which can lead to reduced product tolerance. This can result in non-compliance or dissatisfaction with the treatment from the patient's perspective.

[0017] For this purpose, the MIRVASO® gel formulation, based on methyl parahydroxybenzoate, propylene glycol, carbomer, phenoxyethanol, glycerol, titanium dioxide, sodium hydroxide, and purified water, is unsuitable, for example, for the prevention of radiation-related lesions. This formulation has unoptimized pharmacokinetics, and its activity is limited to 6-12 hours after application. This formulation also contains titanium dioxide particles to interfere with radiation when used for therapeutic purposes, for example, in the prevention or treatment of radiation dermatitis.

[0018] Thus, there is currently a need to develop novel compositions that can limit radiation-related effects, particularly the side effects of radiation therapy for cancer treatment.

[0019] Radiation dermatitis (or radiation-induced dermatitis) can cause painful and distressing lesions that may lead to temporary or permanent discontinuation of treatment.

[0020] On the other hand, there is no consensus on the treatment of acute radiation dermatitis. Numerous solutions have been proposed, but currently, none are sufficiently satisfactory to be adopted.

[0021] For acute grade 1 radiation dermatitis, emollients applied several hours after a radiation session (e.g., DEXERYL® or TOPICREME®) moisturize the skin and provide patients with a brief period of well-being.

[0022] However, it is important to note that this option requires these products not to be applied before the session in order to avoid the risk of bolus effects (localized increases in radiation dose) and burns.

[0023] Several more specific products, such as hyaluronic acid-based creams, TETA® cream, or BIAFINE®, are available for radiation dermatitis lesions. However, it should be noted that these treatments have not been proven effective, and in fact, clinical studies have concluded that they are ineffective.

[0024] Local topical corticosteroids (e.g., DIPROSONE®) should also be applied after the session. The theoretical principle for using these products is to reduce inflammation caused by radiation therapy. While topical corticosteroids do not offer a real benefit in the progression of radiation dermatitis, they are effective in cases of local allergic reactions (e.g., eczema associated with adhesives used for marking).

[0025] In cases of acute radiation dermatitis, the continuation of radiation therapy may be temporarily interrupted if the radiation therapist deems it necessary or preferable based on the progress and priority of the treatment.

[0026] The use of epinephrine as a topically applied adrenergic vasoconstrictor for the prevention of radiation dermatitis in breast cancer patients undergoing radiation therapy has been documented (James F. Cleary et al., Significant suppression of radiation dermatitis in breast cancer patients using a topically applied adrenergic vasoconstrictor, Radiation Oncology, 2017).

[0027] However, such products are instant alcohol-based preparations that evaporate and therefore need to be applied immediately before or up to 20 minutes before radiation therapy.

[0028] Moreover, what is most notable is that its effectiveness is limited by its excessively short duration of action. In the study of the problem, it showed significant benefits in only 50% of patients.

[0029] In cancer treatment where patients are already feeling intolerable, side effects may limit the optimal treatment process and may prevent it. Therefore, there is a genuine need for an effective new formulation that can exert a strong and long-term protective effect and substantially reduce the side effects on the skin caused by radiotherapy.

[0030] Thus, there is a need to develop a new formulation that can cause a strong, long-term, and controlled reduction in skin blood flow restricted to the application site over time, and overcome the above-mentioned drawbacks regarding the tolerance, effectiveness, and compliance of patients receiving radiation, especially cancer patients treated with radiotherapy.

[0031] [Technical Problem] In light of the above circumstances, one of the problems proposed to be solved by the present invention is to develop an optimized topical formulation based on established vasoconstrictors, such as brimonidine tartrate, for the purpose of preventing and greatly reducing the main side effects on the skin caused by radiation, especially cancer treatment by radiotherapy, and improving the duration of activity and efficacy of the vasoconstrictor.

[0032] [Advantages Obtained] The applicant has developed a new topical composition that enables a bioavailability of the vasoconstrictor in the dermis and epidermis for 12 to 14 hours or more while avoiding interference by the radiation of radiotherapy that can reduce the effectiveness to the treated tumor or irradiation field, and improves the duration and efficacy of vasoconstriction by protecting the skin from damage caused by radiation, especially the side effects of treatment by radiotherapy.

[0033] Complex and difficult-to-provide combinations containing low molecular weight (less than 150 g / mol, preferably less than 100 g / mol) polar solvents and high molecular weight (greater than 150 g / mol, preferably 350-650 g / mol) polar solvents have been developed to form vasoconstrictor reservoirs on the skin surface and in the upper layers of the stratum corneum. However, reservoir formation with hydrophilic compounds is far more complex than with lipophilic agents because polar compounds do not distribute into the stratum corneum as readily as lipophilic compounds. Furthermore, hydrophilic compounds themselves are freely distributed in biological tissues and removed to the lower local vascular system by blood circulation. Therefore, an optimal and complex compositional balance needs to be identified to modulate variables such as thermodynamics, surface solubility of the residue, solubility in the stratum corneum, and permeability and persistence in biological tissues (traction effect / solvent drag).

[0034] In addition to the parameters mentioned above, factors important for forming acceptable dosage forms and finished products are also considered when developing the compositions according to the present invention. The compositions according to the present invention are centered on an optimal solvent system that facilitates transdermal administration and provides sufficient physical, chemical, and microbiological stability, in addition to appropriate topical tolerance and cosmetic elegance.

[0035] The topical composition proposed and optimized by the applicant improves the duration (for a period of at least 14 to 24 hours) and the force of the vasoconstriction process, while avoiding a decrease in its effectiveness without interfering with the passage of radiation through the skin.

[0036] The composition according to the present invention enables the formation of a reservoir of polar vasoconstrictor activators in the stratum corneum, a phenomenon usually achieved only by lipophilic molecules, such as corticosteroids, which are typically quickly "washed out" by blood circulation. This allows for a certain degree of persistence in the skin, maximizing the effect with each reapplication and enabling a rapid effect, providing flexible usability for both patients and radiotherapists.

[0037] The optimized composition is particularly suitable for radiation therapy, helping to improve patient compliance and maximize the effectiveness of anti-cancer treatments.

[0038] Furthermore, the novel topical formulations developed by this applicant are less or no irritating than conventional compositions, have improved skin permeability, and exhibit increased solubility of brimonidine tartrate, resulting in good tolerability.

[0039] Ultimately, the pharmaceutical compositions developed by this invention are also economical and can be prepared easily and quickly.

[0040] [Technical solution] The first objective of the solution to the above-mentioned problem is to provide a composition that is aqueous, suitable for topical administration, and contains a vasoconstrictor, wherein the composition is in the form of a hydrogel, and the vasoconstrictor is - Polyethylene glycol combined with propylene glycol and / or dimethyl sulfoxide (DMSO); - A hydrophilic film-forming agent selected from polyvinylpyrrolidone / vinyl acetate copolymer, non-crosslinked, crosslinked or acetic acid form of polyvinylpyrrolidone (PVP), used alone or in combination, preferably polyvinylpyrrolidone / vinyl acetate copolymer as a hydrophilic film-forming agent; and - Glycerin The composition is selected from brimonidine or a salt thereof in a solvent-based phase containing [the specified substance].

[0041] The second objective is a composition according to the present invention for use as a pharmaceutical.

[0042] The present invention and its advantages will be better understood by reading the following description and non-limiting embodiments in conjunction with the accompanying drawings. [Brief explanation of the drawing]

[0043] [Figure 1] This graph shows the skin whitening scores obtained with various hydrogel compositions 19-0155.0058 / F1, 19-0155.0059 / F1, 19-0155.0060 / F1, and 19-0155.0061 / F1. [Figure 2] This graph shows the skin whitening scores obtained with various hydrogel compositions 19-0155.0100 / F1 and 19-0155.0101 / F1. [Figure 3] This graph shows the skin whitening scores obtained for various hydrogel compositions that may contain antioxidants and surfactants: 19-0155.0111 / F1 (control; no antioxidants, no solubilizers), 19-0155.0117 / F1 (1% TWEEN® 80 and 0.1% BHA), 19-0155.0121 / F1 (1.5% TWEEN 80 and 0.1% BHA), 19-0155.0124 / F1 (1% KOLLIPHOR RH40 and 0.1% DL-tocopherol), and 19-0155.0125 / F1 (3% KOLLIPHOR RH40 and 1% DL-tocopherol). [Figure 4] This graph shows the skin whitening scores obtained with various hydrogel compositions 19-0155.0101 / F1, 19-0155.0111 / F1, and 19-0155.0112 / F1. [Figure 5] This graph shows skin whitening scores obtained with various active hydrogel compositions (including brimonidine tartrate) or without an activator (containing only the vehicle). [Figure 6]This graph shows the average erythema score obtained with various active hydrogel compositions (including brimonidine tartrate) or without an activator (containing only the vehicle). [Figure 7] This graph shows the skin whitening scores obtained with the same active hydrogel composition at varying concentrations of the activator (brimonidine tartrate 1.5%, 0.75%, 0.25%, and 0.15% w / w). [Figure 8] This graph shows the skin whitening score obtained with a reference vasoconstrictor. [Figure 9] This graph shows the skin whitening score obtained by comparing the hydrogel composition according to the present invention with the MIRVASO composition (19-0155-0098 / F1) modified with 1.5% w / w brimonidine tartrate, norepinephrine solution, and the MIRVASO® product (0.5% w / w brimonidine tartrate). [Figure 10] This graph shows the skin whitening score obtained by comparing the hydrogel composition according to the present invention, which contains different concentrations of xanthan gum, with the MIRVASO® product. [Modes for carrying out the invention]

[0044] The present invention relates to an aqueous composition containing a vasoconstrictor in a form suitable for topical administration.

[0045] The topical composition according to the present invention is characterized by being in the form of a hydrogel.

[0046] A hydrogel is defined as a hydrophilic, three-dimensional polymer matrix that has the ability to absorb and swell with water without dissolving.

[0047] Typically, one limitation of hydrogels is their incompatibility with lipophilic surfactants or excipients, known for promoting skin delivery and exhibiting good sensory qualities, without the addition of a pharmaceutically acceptable solvent that is inherently hydrophilic. However, if excessive concentrations of inappropriate polar solvents are used in the aforementioned hydrogel compositions, tolerance and sensory properties may be impaired.

[0048] Hydrogels are a galenic form that is advantageously used in topical treatment of skin diseases because they generally exhibit very good tolerability and facilitate the application of active ingredients. These characteristics are related to the use of polymer gels that are high in water content and are effective and biocompatible.

[0049] Such compositions are advantageous for the delivery of hydrophilic surfactants, such as brimonidine and preferably brimonidine tartrate, which promote skin penetration and permeation.

[0050] The hydrogel according to the present invention has low viscosity and can be easily spread to the application site at skin level. This allows for relatively rapid absorption of the finished product, and after rapid drying, it leaves a slight residue on the skin surface, which disappears in less than 10 minutes, preferably less than 5 minutes, more preferably less than 2 minutes, and even more preferably less than 1 minute after application.

[0051] The localized composition according to the present invention has a viscosity between 50 cps and 3000 cps, preferably between 300 cps and 2800 cps, for example, 500 cps, 1000 cps, 1500 cps, 1600 cps, 1700 cps, 1800 cps, 2000 cps, 2500 cps, or 2750 cps.

[0052] The hydrogel according to the present invention provides a moist sensation due to its high water and glycol content, as well as the availability of polymers that modulate the water retention and long-term solubilization of surfactants on the skin surface, thereby extending the duration of the effectiveness of vasoconstriction after application to the skin.

[0053] The topical compositions according to the present invention are - Polyethylene glycol combined with propylene glycol and / or dimethyl sulfoxide (DMSO); - A hydrophilic film-forming agent selected from polyvinylpyrrolidone / vinyl acetate copolymer (KOLLIDON VA64®), non-crosslinked, crosslinked, or acetic acid form of polyvinylpyrrolidone (PVP), used alone or in combination, preferably polyvinylpyrrolidone / vinyl acetate copolymer as a hydrophilic film-forming agent; and - Glycerin The system is characterized by containing a vasoconstrictor selected from brimonidine or a salt thereof in a solvent phase containing the solvent phase.

[0054] "Salt or pharmaceutically acceptable salt" refers to a salt of a compound of interest that is safe and effective for topical use in mammals and possesses the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in certain compounds. Pharmaceutically acceptable acid addition salts include, but are not limited to, salts of hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, bisulfuric acid, phosphoric acid, acidic phosphoric acid, isonicotinic acid, acetic acid, lactic acid, salicylic acid, citric acid, tartaric acid, pantothenic acid, bitartaric acid, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, glucuronic acid, sugar acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and pamoic acid (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)). The specific compounds used in this invention can form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, salts of aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine. For a review of pharmaceutically acceptable salts, see Berge et al., 66 J. PHARM. SCI. 1-19 (1977). "Hydrate" refers to the compound of interest or a pharmaceutically acceptable salt thereof, further containing stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces.

[0055] Preferably, the brimonidine used in the composition according to the present invention is brimonidine tartrate; however, the salt form presents problems from the viewpoint of the stability of the hydrogel formulation.

[0056] Salts, in fact, interact with nonionic surfactants and polymers, reducing their water solubility and consequently impairing the physical stability of semi-solid formulations. In contrast, activators in salt form have relatively high water solubility, which can favorably enable the design and evaluation of aqueous formulations and provide improved performance in terms of sensory and topical tolerance.

[0057] Preferably, brimonidine or a salt thereof, preferably brimonidine tartrate, is used in a concentration between 0.15% and 3.00% by weight of the total weight of the composition to obtain improved efficacy and duration of effect up to 24 hours after application, while preventing any risk of systemic exposure.

[0058] Preferably, the composition according to the present invention contains brimonidine or a salt thereof, preferably brimonidine tartrate, at a concentration between 0.50% and 2.50% by weight of the total weight of the composition, preferably between 0.75% and 1.50% w / w, more preferably between 1.00% and 1.50% w / w, and even more preferably between 1.00% or 1.50% w / w.

[0059] The concentration of brimonidine, preferably brimonidine tartrate, and the applied dose can be advantageously adapted according to the application site.

[0060] In fact, the barrier formed by the skin, particularly the stratum corneum through which the ointment is absorbed, is thicker on the hands and feet than on the scalp, and of moderate thickness on other parts of the body, especially the chest. Therefore, for the same dose, the preferred concentration is advantageously lower on the scalp, in the range of 0.15–0.5% w / w, compared to the concentrations used on other parts of the body, such as 0.75–1.5% w / w on the chest, or, for example, 1.5–3% w / w on the hands and feet.

[0061] The topical composition according to the present invention is characterized by containing polyethylene glycol (PEG) in combination with propylene glycol and / or dimethyl sulfoxide (DMSO).

[0062] Low molecular weight polyethylene glycol (PEG) is commonly used in topical products because it is a solvent that is effective for many types of active ingredients; however, it is not necessarily the most effective excipient for topical administration.

[0063] This is primarily due to its high polarity and molecular weight, which limit absorption by the skin. These properties limit the potential of the solvent as a vehicle (traction effect) for the activator in the skin. This usually occurs when the solvent dissolves in the skin and then transports the dissolved solute to the skin.

[0064] Furthermore, PEG's high solubilizing ability can result in suboptimal thermodynamics for topical administration, and when used at high concentrations, it cannot be used to facilitate product transformation, often associated with the evaporation of volatile components such as water, in order to promote release through the skin. Overall, while high concentrations are possible, these properties can reduce delivery efficiency, and a large portion of the applied dose of the topical agent remains on the skin surface or is lost to the surroundings by contact migration.

[0065] Increased delivery efficiency and a small applicable dose can limit the need for dose increases and the use of high PEG concentrations to achieve the target level of transdermal delivery.

[0066] The permeability and penetration of PEG have also been shown to depend on its molecular weight.

[0067] Nevertheless, in the hydrogel composition according to the present invention, PEG is necessary for topical formulation.

[0068] Low molecular weight PEGs up to PEG-600, such as PEG-200, PEG-300, PEG-400, or PEG-400SR, are preferably used, more preferably PEG-400, and even more preferably PEG-400SR, which advantageously enhances the stability and tolerance of the hydrogel composition according to the present invention by reducing the potential for irritation, removing polar impurities, and reducing the interaction between the excipient and the activator (brimonidine tartrate) and the subsequent degradation of the activator.

[0069] PEG-400 or PEG-400SR, due to their molecular weight and high polarity (low partition coefficient), have relatively low permeability to the stratum corneum, but are PEGs that reduce the precipitation rate of activators on the skin surface and in the upper layers of the stratum corneum for surface solubilization, and are preferably used in the hydrogel composition according to the present invention. This is advantageous for long-term administration of brimonidine tartrate to the viable layers of the skin, particularly to the dermal nerve plexus where the target site of brimonidine tartrate is located. PEG-400 or PEG-400SR has sufficient solubility to promote good retention of brimonidine tartrate in solution on the skin surface and in the upper layers of the stratum corneum.

[0070] Preferably, the composition according to the present invention contains PEG at a concentration of 1 to 20% by weight, preferably 5 to 15% by weight, and more preferably 10% by weight, of the total weight of the composition.

[0071] Propylene glycol (PG, 1,2-propanediol) is a colorless, transparent, hygroscopic liquid widely used as a solvent and preservative in various oral and parenteral pharmaceutical formulations.

[0072] PG is known as a better general solvent than glycerin and dissolves a wide variety of materials, including corticosteroids, phenols, barbiturates, vitamins (A and D), most alkaloids, and many local anesthetics.

[0073] On the other hand, PG exhibits 50% of the solubilizing ability of glycerin in the case of brimonidine tartrate.

[0074] As an antibacterial agent, PG has similar effects to ethanol, but its effectiveness against mold is slightly lower, and its profile is comparable to that of glycerin.

[0075] PG also exhibits some degree of volatility; small amounts evaporate upon application to the skin or at least within 37 hours of application, but the vast majority penetrate the stratum corneum and enter the deeper layers of the skin.

[0076] The relatively rapid permeability and volatility of PG into the stratum corneum depletes the residual vehicle of its solvent, increasing the thermodynamic activity of the activator in the vehicle and regulating the driving force of diffusion. Furthermore, the permeability and penetration of PG can disrupt the lipid barrier of the stratum corneum, reducing diffusion resistance.

[0077] Thus, PG possesses favorable physical and chemical properties for skin permeability and penetration, and is absorbed through the skin. Therefore, solutes that are readily soluble in PG (i.e., have high affinity for the solvent / vehicle) can advantageously benefit from improved skin permeability or traction effects via solvent-resistant mechanisms.

[0078] Despite the literature documenting data on various compounds demonstrating that transdermal delivery of pharmaceutically relevant compounds can be facilitated by prostaglandins, predicting the stability, permeation efficiency of activators, particularly brimonidine tartrate, and tolerance of topical compositions obtained using the present invention that are effective, stable, and pharmaceutically acceptable in complex solvent systems is not obvious to those skilled in the art.

[0079] For an even stronger reason, PG is known to penetrate the skin more rapidly than most surfactants, and therefore, the precipitation of the surfactant on the skin surface limits the duration of its action.

[0080] In addition, the concentration of prostaglandins (PGs) used in vivo is usually limited to approximately 20% w / w or less to avoid local irritation and systemic toxicity issues.

[0081] In the topical compositions according to the present invention, the choice to use PG as a solvent and penetration enhancer is not readily predictable based on solubility and other vehicle-related variables.

[0082] Preferably, the composition according to the present invention contains PG at a concentration of 5% to 40% by weight, preferably 10% to 30% by weight, more preferably 15% to 25% by weight, and even more preferably 20% by weight, of the total weight of the composition.

[0083] Dimethyl sulfoxide (DMSO) is a colorless, odorless, water-miscible, and hygroscopic aprotic solvent. DMSO is known for its ability to dissolve many small polar and nonpolar molecules, in addition to several polymers, and as an agent that facilitates the permeation of hydrophilic and lipophilic compounds, including antivirals, steroids, and antibiotics.

[0084] Regarding DMSO, • Regulation of the intracellular higher-order structure of keratin from helical to β (beta) sheet. • Replacement of bound water from keratin, • Extraction of skin lipids, • Interaction with lipid groups at the polar head, resulting in reduced lipid fluidity and diffusion resistance. • Interaction with lipid alkyl chains in the stratum corneum, • Increased distribution of vehicles in the stratum corneum via increased solubility of permeants in aqueous domains between lipid bilayers. Several possible mechanisms of skin penetration, including [specific mechanism], have been described.

[0085] It is well known that DMSO easily penetrates and impregnates the skin.

[0086] Surprisingly, DMSO can also provide a solvent tracking effect regarding the delivery of activators through the skin.

[0087] The effectiveness of DMSO depends on its concentration level. Generally speaking, cosolvent systems containing DMSO concentrations above 60% w / w provide optimal efficiency.

[0088] On the other hand, such relatively high concentrations of DMSO can most notably cause erythema and irritation.

[0089] These factors limit the use of high concentrations of DMSO in topical and transdermal compositions.

[0090] DMSO can be used at low concentrations, for example, at a concentration of 45% in the topical analgesic product PENNSAID®, as an active solubilizer for the stratum corneum.

[0091] In the composition according to the present invention, DMSO is preferably used in a limited concentration range, less than 20% w / w, preferably less than 10% w / w, and more preferably 5% w / w, compared to conventional compositions.

[0092] Advantageously, the relatively high solubility of brimonidine tartrate in DMSO, combined with its limited concentration, makes DMSO a preferred solvent for the compositions according to the present invention.

[0093] In the hydrogel composition according to the present invention, controlling the ratio of PEG:PG and / or PEG:DMSO is particularly advantageous.

[0094] Excessively high concentrations of PEG, exceeding 50% w / w, when combined with PG and / or DMSO, have a negative impact on the vasoconstrictive intensity of brimonidine tartrate.

[0095] In one preferred embodiment, PEG and PG are used in a ratio of 1:1 to 1:5, preferably 1:2.

[0096] In one preferred embodiment, PEG and DMSO are used in a ratio of 1:1 to 5:1, preferably 2:1.

[0097] According to certain preferred embodiments of the hydrogel composition of the present invention, PEG is used in combination with PG alone, and more preferably in combination with PEG-400SR and PG.

[0098] Preferably, the composition according to the present invention contains propylene glycol (PG) at a concentration of 20% by weight of the total weight of the composition, and polyethylene glycol (PEG) at a concentration of 10% by weight of the total weight of the composition.

[0099] The topical compositions according to the present invention are characterized by comprising, alone or in combination, a hydrophilic film-forming agent selected from polyvinylpyrrolidone / vinyl acetate copolymer, non-crosslinked, crosslinked, or acetic acid form of polyvinylpyrrolidone (PVP).

[0100] Preferably, the compositions according to the present invention contain, alone or in combination, a hydrophilic film-forming agent at a concentration of 0.1% to 1.5% by weight, preferably 0.25% to 1.4% by weight, more preferably 0.5% to 1.3% by weight, even more preferably 0.75% to 1.25% by weight, and even more preferably 1% by weight, of the total weight of the composition.

[0101] Preferably, the topical composition according to the present invention contains polyvinylpyrrolidone / vinyl acetate copolymer (KOLLIDON VA64®) as a hydrophilic film-forming agent.

[0102] Preferably, the composition according to the present invention contains polyvinylpyrrolidone / vinyl acetate copolymer (KOLLIDON VA64®) at a concentration of 0.1% to 1.5% by weight, preferably 0.25% to 1.4% by weight, more preferably 0.5% to 1.3% by weight, more preferably 0.75% to 1.25% by weight, and even more preferably 1% by weight of the total weight of the composition.

[0103] The topical composition according to the present invention is characterized by further comprising glycerin.

[0104] Glycerin (glycerol) is known as a moisturizer that can enhance the water retention of the stratum corneum and improve hydration.

[0105] Glycerin is known and used to support the normal function of the skin barrier, promote skin elasticity and plasticity, improve skin smoothness, and provide anti-irritant effects. Glycerin can actually draw water from the epidermis and the air into the stratum corneum.

[0106] Although glycerin, due to its relatively high polarity, does not penetrate the skin to the same extent and depth as propylene glycol, it can increase water content by accumulating and forming reservoirs in the hydrophilic regions of the stratum corneum.

[0107] The interaction between glycerin and the stratum corneum, its distribution in the skin, and its relatively high solubility in brimonidine tartrate (twice as solubility as propylene glycol) offer advantages in terms of improved transdermal administration and long-term permeability without causing stickiness on the skin surface.

[0108] Preferably, the composition according to the present invention contains glycerin at a concentration of 1% to 20% by weight, preferably 2% to 15% by weight, more preferably 3% to 10% by weight, and even more preferably 4% by weight, of the total weight of the composition.

[0109] In a particularly advantageous manner, the combination of PG and glycerin improves the distribution of the activator, preferably brimonidine tartrate, in the stratum corneum.

[0110] Furthermore, DMSO offers similar functionality to PG, but with greater solubility in brimonidine tartrate. This difference in solubility is advantageous for administering the product through the skin.

[0111] Preferably, the topical composition according to the present invention further comprises a gelling agent selected from xanthan gum or hydroxyethylcellulose (HEC) which can be used alone or in combination, and more preferably, the topical composition according to the present invention comprises at least xanthan gum as the gelling agent.

[0112] Preferably, the composition according to the present invention preferably contains xanthan gum and / or HEC in combination at a concentration of 0.1% to 1.5% by weight of the total weight of the composition, wherein the xanthan gum is contained at a concentration of 0.2% to 1% by weight, more preferably 0.2% to 0.75% by weight, and even more preferably 0.2 to 0.5% by weight, and the HEC is contained at a concentration of 0.3 to 0.5% by weight.

[0113] Table 1 below shows examples of hydrogel compositions according to the present invention, comprising xanthan gum (XANTHANE FNCSP-PC®) and / or HEC (NATROSOL 250HHX®).

[0114] [Table 1]

[0115] The flexible mixed film, in addition to other non-volatile solvents, PG and PEG, is favorably formed on the skin surface with xanthan gum and / or HEC, as well as polyvinylpyrrolidone / vinyl acetate copolymer (KOLLIDON VA64®), enabling the formation of a reservoir for brimonidine, preferably brimonidine tartrate, thereby slowing the precipitation of brimonidine and extending its duration of action.

[0116] Preferably, the topical composition according to the present invention also includes a natural or synthetic antioxidant or a free radical scavenger.

[0117] The antioxidant is selected from butylated hydroxyanisole (BHA), DL-tocopherol, butylated hydroxytoluene (BHT), propionaldehyde, palmitate, ascorbate, or glutathione, either alone or in mixtures, and is preferably selected from BHA and / or DL-tocopherol.

[0118] In the hydrogel composition according to the present invention, the antioxidant is used in a concentration between 0.01% and 4.0% by weight of the total weight of the composition, more preferably between 0.1% and 1.0% w / w, and even more preferably at 0.1%. For example, BHA is preferably used at 0.1% w / w and / or DL-tocopherol at 0.1% w / w.

[0119] Preferably, the composition according to the present invention contains a free radical scavenger, preferably amiphostin, at a concentration of 0.1% to 3% by weight of the total weight of the composition, for example, 2.5% w / w.

[0120] Preferably, if the topical composition according to the present invention contains an antioxidant, it also contains polysorbate, preferably polysorbate 80 (TWEEN80 SR®) and / or polyoxyethylene hydrogenated castor oil 40 (KOLLIPHOR RH40®).

[0121] Preferably, the topical composition according to the present invention contains polysorbate, preferably polysorbate 80 (TWEEN80 SR®) in an amount of less than 5% by weight, more preferably 1 to 1.5% by weight, and even more preferably 1% by weight of the total weight of the composition, and / or polyoxyethylene hydrogenated castor oil 40 in an amount of less than 3% by weight, preferably 1% by weight of polyoxyethylene hydrogenated castor oil 40 of the total weight of the composition.

[0122] Preferably, the topical composition according to the present invention further comprises, alone or in combination, oleyl alcohol (KOLLICREAM OA®) and vitamin E.

[0123] The incorporation of a hydrophilic solvent phase containing PG and glycerin, which have hygroscopic, moisturizing, and skin conditioning properties, helps improve the solubility of brimonidine tartrate in the stratum corneum and increase the water content of the stratum corneum.

[0124] The advantageous incorporation of antioxidants improves the stability of the activator.

[0125] Therefore, the hydrogel composition according to the present invention improves and extends the transdermal delivery of brimonidine tartrate and helps meet the needs of patients by providing sufficient long-lasting local vasoconstriction and superior protection of the epidermis and dermis compared to oxygen-reactive and inflammatory mediators.

[0126] The compositions according to the present invention are easy to apply and can be applied to potentially irritated skin.

[0127] These dry rapidly, leaving only a very small residue on the skin.

[0128] The topical composition according to the present invention has a pH between 4.0 and 6.0, preferably between 4.2 and 5.5, more preferably between 4.3 and 5.0, and even more preferably between 4.5.

[0129] Another object of the present invention relates to a hydrogel composition according to the present invention for its use as a pharmaceutical.

[0130] Preferably, the hydrogel composition according to the present invention is used for the prevention and / or treatment of radiation-induced damage, the radiation being of photons or protons, or being natural, therapeutic or accidental, and including ultraviolet (UV) radiation, i.e., UVA and UVB which can cause sunburn, visible radiation, infrared radiation (IR), or even ionizing radiation, such as X-rays and α, β, γ rays, or even proton beams.

[0131] Preferably, the hydrogel composition according to the present invention is used for the prevention and / or treatment of radiation-induced dermatitis, particularly in treatment with radiotherapy, for example, X-ray or proton radiation. [Examples]

[0132] The present invention will be illustrated below with reference to examples.

[0133] [Example 1] Measurement of saturation solubility in pure solvent (method) Saturated solutions were prepared by adding an excess amount of the active pharmaceutical ingredient to various solvents and storing the sample in a sealed container at room temperature for 24 hours while continuously stirring the sample.

[0134] Most samples were stirred using a magnetic stirrer, but viscous samples (e.g., pure glycerin) were stirred using a rotary mixer. The speed of the rotary mixer was adjusted to ensure proper mixing of the sample, which generally involved slower rotation speeds.

[0135] After equilibration, the sample was centrifuged or filtered, and brimonidine tartrate was quantified using a Thermo Scientific Dionex U3000 UPLC-UV system. The chromatography conditions are described below. • Column: Sunfire C18 150mm x 4.6mm, 3.5μm Column temperature: 40°C ·Injection volume: 5μl ·Flow rate: 0.8ml / min • UV detection: 246nm

[0136] (result) Table 2 below summarizes the saturation solubility results for each solvent used separately, as determined by UPLC-UV.

[0137] [Table 2]

[0138] (Conclusion) The results suggest that DMSO is an excellent solvent for brimonidine tartrate. Saturation was not reached even after the addition of 8.5% w / w brimonidine tartrate.

[0139] Water is considered the next best solvent; the activity of the salt form likely works in favor of its solubility in water.

[0140] Next, in descending order, were glycerin (GLY), glucan, propylene glycol (PG), and PEG-400.

[0141] The solubility observed for other solvents was remarkably low, and the results for the solubility of brimonidine tartrate were not satisfactory.

[0142] Interestingly, well-known solvents, such as Transcutol and DMI, appear to be far less effective than glycerin or propylene glycol against brimonidine tartrate.

[0143] [Example 2] Measurement of saturation solubility in a solvent mixture (method) A saturated solution was prepared in the same manner as in Example 1, incubated, and measured.

[0144] (result) Table 3 below summarizes the saturation solubility results for each solvent used separately, as determined by UPLC-UV.

[0145] [Table 3]

[0146] (Conclusion) As expected, non-aqueous solvent mixtures are thought to have lower solubility power than mixtures containing water.

[0147] Nevertheless, the results obtained suggest that the non-volatile mixture containing PG / PEG-400 / GLY / PVP (20:10:5:1) was able to solubilize approximately 22% of the activator compared to the aqueous mixture PG / PEG-400 / GLY / PVP / water (20:10:5:1:40). This indicates that even after the water evaporates, the non-volatile polar component of the aqueous gel in the residual formulation may have some ability to dissolve brimonidine tartrate in the skin surface and stratum corneum.

[0148] When using brimonidine tartrate at a concentration of 1% or 1.5%, the activator may be approximately 30% or 50% saturated, respectively, in the aqueous solvent phase of the initial formulation before application. However, when the formulation was applied to the skin surface, the water evaporated relatively quickly.

[0149] Therefore, while the results obtained appear favorable in terms of the physical stability of the formulation, this is not necessarily the case with respect to conventional skin distribution, as the thermodynamic activity was relatively low.

[0150] [Example 3] Measurement of stability in a single solvent and a preliminary mixture of solvents The solvent combinations were prepared as shown in Table 4 below. To facilitate evaluation, 0.1% brimonidine tartrate was added to each mixture. The samples were stored at room temperature, 40°C, and 50°C for one month, and samples were taken at intervals of T=0 and T=1 month.

[0151] [Table 4]

[0152] Table 5 below summarizes the fit data generated in this study.

[0153] [Table 5]

[0154] The results showed that the mean was between 99.36% and 101.45%, and the relative standard deviation was less than 1%.

[0155] The solvent blend without Glucam E20 showed the most favorable stability profile, and glycerin was considered to improve stability. The stability of brimonidine tartrate improved when Glucam E10 was included in the composition at a concentration of 5%. The measured values ​​of brimonidine tartrate tended to decrease as the Glucam concentration increased. The most stable solvent mixture was obtained against M8 (water, 30% Transcutol), followed by M1 (water, 10% DMSO, 5% Glucam E10, and 5% glycerin).

[0156] The data obtained showed that using Glucam E10 and E20 increased the risk of brimonidine tartrate destabilization. On the other hand, Transcutol, DMSO, and glycerin showed acceptable compatibility profiles.

[0157] [Example 4] Evaluation of the skin whitening effect of various solvents in the formulation according to the present invention In the formulation according to the present invention, propylene glycol (PG), dimethyl sulfoxide (DMSO), and polyethylene glycol 400 (PEG-400) were identified as the target solvent for brimonidine tartrate.

[0158] The concentrations of these solvents varied across various low-viscosity hydrogel formulations (Table 6), and skin whitening was evaluated using a skin whitening model. The selection of different concentrations for each solvent tested was based on solubility data and consideration of local tolerance. For example, DMSO is a better solvent than PG for brimonidine tartrate, so a lower concentration was selected to more favorably improve the thermodynamic activity of the residual formulation.

[0159] In these sample hydrogel formulations, hydroxyethylcellulose (HEC, Natrasol HHX) was used as the gelling agent.

[0160] [Table 6]

[0161] Figure 1 shows the skin whitening score in graph form (average of 3 replicates), and the trend was used to interpret the data.

[0162] The results suggest that formulations containing PG resulted in a higher peak whitening score and a more rapid onset of action compared to DMSO equivalents.

[0163] The best results were obtained with a formulation containing 20% ​​PG and 10% PEG-400 (19-0155.0059 / F1), which resulted in optimal skin whitening along with rapid onset and long duration of action. The skin whitening profile obtained with the 19-0155.0059 / F1 formulation shows the best balance of rate, intensity, and duration of skin whitening action.

[0164] [Example 5] Evaluation of the skin whitening effect of various polymers in the formulation according to the present invention The effect of the base of several formulations on skin whitening was tested using various low-viscosity hydrogel formulations (Table 7). All tested formulations contained xanthan gum, which offers advantages in terms of stability.

[0165] [Table 7]

[0166] Based on the results obtained in this manner and illustrated in Figure 2, the two low-viscosity hydrogels tested yielded an acceptable skin whitening profile. The same solvent system (20% PG + 10% PEG-400) was used for both compositions, but the polymer combinations differed in that formulation 19-0155.0100 / F1 contained KOLLIDON VA-64®, NATROSOL HEC®, and xanthan gum, while formulation 19-0155.0101 / F1 contained only xanthan gum. Formulation 19-0155.0100 / F1 showed higher viscosity and better skin adhesion after application than formulation 19-0155.0101 / F1.

[0167] Formulation 19-0155.0100 / F1 showed a more pronounced whitening, while formulation 19-0155.0101 / F1 showed a slightly longer-lasting tendency towards whitening.

[0168] Significant differences between compositions were observed with respect to sensory perception and drying time.

[0169] Formulation 19-0155.0100 / F1, containing KOLLIDON VA-64®, NATROSOL HEC®, and xanthan gum, is somewhat less desirable in terms of sensory quality due to its slightly sticky texture upon application and the long drying time required, but it offers a long duration of action, thereby enabling a prolonged vasoconstrictive effect.

[0170] [Example 6] Evaluation of the skin whitening effect of various antioxidants in the formulation according to the present invention In developing compositions according to the present invention, it is necessary to ensure suitable chemical stability. pH is an important factor in supporting chemical stability. Based on preliminary studies and the natural pH of skin, the target value was set at pH 4.0 to 5.5. Another important factor is oxidation, and screening of antioxidants was included as a preliminary step to prevent or control oxidation.

[0171] The first step in the antioxidant selection method is to evaluate the physical compatibility of the antioxidant with the formulation of interest. Many effective antioxidants, such as butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), propyl gallate, and tocopherol, are inherently lipophilic. Therefore, these components dissolve relatively easily or reversibly adapt to the typical oil phase of an emulsion. However, their hydrophobicity and low water solubility make their incorporation into hydrogels problematic and complex. Nevertheless, for preliminary testing, two antioxidants, BHA and tocopherol, were screened, more specifically, in various hydrogel formulations according to the present invention.

[0172] BHA is a highly lipophilic antioxidant widely used in both bulk oils and oil-in-water emulsions. BHA has been reported to possess antimicrobial activity and has shown co-antioxidant activity through the regeneration of other antioxidants, such as BHT and α-tocopherol. BHA is often used in combination with BHT and propyl gallate, as well as with supplements or synergists, such as citric acid.

[0173] Natural vitamin E is called RRR-α-tocopherol (commonly known as d-α-tocopherol), and its synthetically produced form is all-rac-α-tocopherol (commonly known as dl-α-tocopherol). α-tocopherol is a lipophilic antioxidant that plays a crucial role in a wide range of biochemical and physiological processes, and it has been selected as a proton donor. α-tocopherol has synergistic effects with vitamin C and other natural antioxidants. The effects of α-tocopherol regeneration in neutral and acidic environments have also been reported.

[0174] Despite the presence of PG and PEG-400, which are potentially suitable solvents for lipophilic antioxidants, the use of one or more additional solubilizers may be advantageous. Two commonly used surfactants as solubilizers, TWEEN80® (polysorbate 80) and KOLLIPHOR RH40® (polyoxyethylene hydrogenated castor oil 40), were screened.

[0175] Table 8 below lists the compositions tested in this embodiment.

[0176] [Table 8] JPEG0007875608000009.jpg79170

[0177] The color of low-viscosity hydrogels was evaluated using color evaluation with reference solutions standardized according to the European Pharmacopoeia (B, BY, Y, R, GY). The activator brimonidine tartrate imparted a pH-dependent yellow color, while clear gels acquired an intermediate (medium) color to facilitate color evaluation.

[0178] Furthermore, the formulation demonstrated sufficient stability, as the increase in color intensity at 40°C after 2-3 months was minimal.

[0179] The pH of the composition remains within the acceptable range of 4.5 to 5 even after storage at 40°C for 3 months.

[0180] The results showed that all formulations containing 0.1% BHA or 0.1% tocopherol were clear.

[0181] On the other hand, formulation 19-0155.0125 / F1 is cloudy in appearance, which may be related to the increased level of antioxidant (1% tocopherol) compared to the other compositions tested. The concentration of KOLLIPHOR RH40® needs to be increased to solubilize the high tocopherol load.

[0182] Even when the tocopherol content was reduced from 1% to 0.5%, the composition showed turbidity (data not shown).

[0183] Ultimately, even high concentrations of solubilizers were unable to solubilize 1% BHA.

[0184] Despite the issues associated with the solubilization of high concentrations of tocopherol, formulation 19-0155.0125 / F1 was also tested with other compositions in Table 8 in a skin whitening model to evaluate the effects of 3% KOLLIPHOR RH40® and 1% tocopherol on skin whitening. It is important to note that all compositions tested in this example contain 20% PG, 4% glycerin, 10% PEG-400, 0.2% xanthan gum, and 1% KOLLIDON VA64®.

[0185] Figure 3 shows the results obtained (based on the mean ± standard deviation of the three copies).

[0186] All formulations containing 0.1% BHA or 0.1% tocopherol and 1.5% or less of TWEEN80® or 1% KOLLIPHOR RH40® behaved similarly to the so-called control formulation 19-0155.0111 / F1. Each of these compositions exhibited a similar skin whitening profile, achieving a maximum score of 3.0 over 2–4 hours. The rate of whitening activity was also similarly acceptable, with scores of 2.0 or higher after 3 hours. The duration of effect was also very satisfactory, with skin whitening scores of 0.5–1 after 24 hours. Therefore, these compositions provided excellent skin whitening performance.

[0187] On the other hand, formulation 19-0155.0125 / F1 exhibited significantly less favorable behavior than the other compositions, with a much slower onset, lower peak, and shorter whitening time. In fact, whitening returned to baseline after 16 hours. It was hypothesized that high concentrations, i.e., 3.0% KOLLIPHOR RH40®, could be involved in, and actually alter, the thermodynamic activity of brimonidine tartrate, as well as its release from the primary and / or residual composition. A similar effect on skin whitening was observed when 5% TWEEN80 was used in combination with 0.1% BHA in formulation 19-0155.0112 / F1 (Table 7), as shown in Figure 4.

[0188] The results obtained indicate that antioxidants at concentrations of 0.1% BHA and tocopherol or less could be advantageously incorporated into the hydrogel composition according to the present invention, containing 1.5% TWEEN80® and up to 1% KOLLIPHOR RH40®, without physical instability or impairing the appearance, intensity, or duration of skin whitening.

[0189] On the other hand, when the concentration of KOLLIPHOR RH40 (registered trademark) was increased to 3%, a significant decrease in skin whitening performance was observed.

[0190] [Example 7] Evaluation of the skin whitening effect of various low-viscosity hydrogel compositions using an in vivo vasoconstriction model. Table 9 below shows the compositions and physical stability of the low-viscosity hydrogels tested. These formulations are based on compositions 19.0155-0101 and 19.0155-0121 after positive stability and performance evaluation.

[0191] [Table 9]

[0192] Each composition was tested three times using the in vivo vasoconstriction protocol described below.

[0193] Each 60-microliter dose of the composition was applied once to the upper chest at 8 a.m. using a volumetric pipette to a 10 cm² area defined by a plastic O-ring, in a blinded, randomized manner.

[0194] After application, a 30-second massage was followed, and then the applied product was allowed to dry for 10 minutes.

[0195] The bleaching score on a conventional scale of 0 to 3 (3 = maximum) was measured 1, 2, 3, 4, 8, 10, 12, 14, 16, and 24 hours after application.

[0196] Figure 5 illustrates the results obtained. The results showed that formulations containing 1.5% w / w brimonidine tartrate resulted in a high level of long-term skin whitening, which is indicative of vasoconstriction.

[0197] Both hydrogel formulations (19-0155.0135 / F1 and 19-0155.0134 / F1) produced similar vasoconstriction profiles. The degree of vasoconstriction was also similar, at approximately 1.5 after 1 hour and peaking at approximately 4 hours. The intensity of vasoconstriction remained at approximately 3.0 up to 14 hours after application, decreasing to 1.0–1.5 after 24 hours.

[0198] [Example 8] The active compositions containing brimonidine tartrate and vehicle, listed in Table 10, were evaluated using a UV-induced erythema model.

[0199] The composition was applied using the protocol described below. The method included application to three healthy volunteers the night before UV irradiation and two hours before UV irradiation.

[0200] The individual minimum erythemal dose (MED) for each subject was determined 24 hours prior to the experiment. Nine sub-regions were defined on the dorsal torso of each subject, and the composition was applied to these regions at a dose of 5 mg / cm². UV doses were administered at 1 × MED (MED or DEM [minimum erythemal dose]), 2 × MED (2MED), and 3 × MED (3MED) and assimilated to this dose.

[0201] Experimental readings were performed 24 hours after irradiation using investigator erythema scores and a chromameter.

[0202] [Table 10]

[0203] Figure 6 summarizes the average erythema score for each composition.

[0204] The active composition containing 1.5% brimonidine tartrate showed a substantial reduction in erythema score compared to the vehicle. Further advantages in anti-erythema effects were observed when 1.5% w / w brimonidine tartrate was combined with antioxidants. BHA and α-tocopherol were used as antioxidant models at concentrations of 0.1% and 1% w / w, respectively.

[0205] The hydrogel composition according to the present invention exhibited effective anti-erythematous properties in a UV-induced erythema model. When 1.5% w / w brimonidine tartrate was combined with an antioxidant, BHA, or α-tocopherol, additional benefits were observed with respect to the treatment and / or prevention of erythema. The most potent anti-erythematous effect was observed when brimonidine tartrate was combined with 1.0% of each antioxidant.

[0206] [Example 9] Performance test - In vivo human skin whitening (vasoconstriction) model An in vivo vasoconstriction model was adapted for the study, and the performance of the topical formulation according to the present invention was evaluated in terms of the onset, amplitude, and duration of the effect.

[0207] Typically, the product is applied to the ventral side of the forearm, and an arbitrary score of 0, 1, 2, or 3 is assigned based on skin whitening.

[0208] The tests conducted were: • Implementation and calibration of a skin whitening model • The effect of the application dose of each tested formulation. • Effect of loading dose of brimonidine tartrate in tested hydrogel formulations • The effect of medication frequency on skin whitening in a skin whitening model. This includes a step-by-step approach.

[0209] (Methodology of Skin Whitening Tests) The parameters of the model used are listed below. • Products will be applied randomly, applied at 8am. ·Applicable ·Upper chest • 60 microliter formulation using a volumetric pipette • The specified surface area (10 cm²) using a plastic O-ring 2 ) After applying the product, massage for 30 seconds and allow to dry for 10 minutes.

[0210] (evaluation) • 10 points at the time of ranking • 1, 2, 3, 4, 8, 10, 12, 14, 16 and 24 hours after application • Investigator's whitening score: Scale from 0 to 3 (3 = maximum)

[0211] (Setting up and calibrating the skin whitening test) To evaluate the performance (sensitivity, specificity, and extent) of the skin whitening model, several preliminary experiments were conducted using a low-viscosity hydrogel formulation base.

[0212] The preliminary experiment was • The amount of the test substance applied to the standard test area, i.e., 60 μl, 30 μl, and 15 μl per 10 cm². • Variations in the loading dose of brimonidine tartrate, i.e., 1.5% w / w, 0.75% w / w, 0.25% w / w, and 0.15% w / w • Medication frequency / medication schedule It included an evaluation of [the subject].

[0213] (Effects of loading dose of brimonidine tartrate in hydrogel test substance in skin whitening model) Table 11 below details the compositions used.

[0214] [Table 11]

[0215] The model was able to arrange the formulations in an appropriate rank order related to the concentration of brimonidine tartrate (Figure 7). The formulations were then ranked from highest to lowest whitening score. • 1.5% brimonidine tartrate > 0.75% brimonidine tartrate > 0.25% brimonidine tartrate ~= 0.15% brimonidine tartrate They were ranked in the following order.

[0216] This classification is based on the formulation. ·19-0155.0111 / F1>19-0155.0128 / F1>19-0155.0129 / F1~=19-0155.0130 / F1 It is equal to.

[0217] Formulation 19-0155.0111 / F1, containing 1.5% brimonidine tartrate, was the only formulation to reach the highest skin whitening score of 3.0, and remained above 1.0 even after 12 hours.

[0218] [Example 10] Performance of the reference product in a skin whitening model A skin whitening model (vasoconstriction) was tested using a reference pharmaceutical product known to induce skin whitening / vasoconstriction. The initial study was MIRVASO® Gel (0.5% w / w Brimonidine Tartrate) • Clobetasol propionate cream, 0.05% w / w • A norepinephrine hydrochloride solution (70:30 ethanol:82 mg / ml in water) similar to the formulation used by Fahl (Effect of topical vasoconstrictor exposure upon tumoricidal radiotherapy. Int J Cancer;135(4):981~988, 2014) and Cleary et al. (Significant suppression of radiation dermatitis in breast cancer patients using a topically applied adrenergic vasoconstrictor. Radiation Oncology, 2017). It was done using [a specific method / tool].

[0219] The skin whitening model allows for differentiation of the skin whitening ability brought about by several activators applied in various formulations, in terms of the appearance, intensity, and duration of skin whitening.

[0220] The model demonstrates sufficient reproducibility and discriminatory performance during the pharmaceutical screening phase.

[0221] Clobetasol propionate cream was selected as a clearly defined product / activator involved in skin whitening. In fact, the in vivo efficacy and bioequivalence of topical corticosteroids (1997 FDA guidelines, https: / / www.fda.gov / media / 70931 / download) are evaluated using this vasoconstrictive effect.

[0222] Figure 8 shows the skin whitening data for MIRVASO® gel, clobetasol propionate cream 0.05% w / w, and epinephrine HCl solution (70:30 ethanol:82 mg / ml in water) in graph form.

[0223] MIRVASO® gel did not cause significant whitening. This was expected because MIRVASO® gel was designed to be applied to relatively thin and sensitive facial skin to treat rosacea. As a rule, the skin of rosacea patients is sensitive, so these products did not contain potentially high concentrations of skin-penetrating agents. Furthermore, facial skin is thinner than chest skin and therefore has a lower barrier to penetration and permeation. The intensity and duration of action were insufficient to meet the desired requirements for radiation-induced dermatitis.

[0224] Norepinephrine (noradrenaline) solution rapidly produced moderate skin whitening one hour after application, but the effect began to diminish after a 4-hour observation interval. Whitening was less than 0.5 after 10 hours and returned to baseline after only 16 hours. The initial effect was promising, but the duration and intensity of the effect were insufficient.

[0225] Unlike the polar molecule norepinephrine and its aqueous ethanol vehicle, clobetasol propionate cream showed a gradual onset of action, gradually increasing to a peak whitening score of 2.0 over 2 hours between 14 and 16 hours. A rapid decline in whitening began at 16 hours and returned to baseline at 24 hours. The gradual onset of whitening action of clobetasol may be related to the physical and chemical properties of the activator, meaning its lipophilic nature results in reservoir formation and a more limited distribution in living epidermis compared to the more hydrophilic norepinephrine. It is also important to note that the pharmacodynamic mechanisms of vasoconstriction differ between clobetasol propionate and norepinephrine.

[0226] Furthermore, a modified MIRVASO-type formulation was prepared with a high dose of 1.5% w / w brimonidine tartrate (19-0155-0098 / F1). This evaluation was performed to assess the effect of increased dose on skin whitening in a vehicle similar to MIRVASO. In the same experiment, the low-viscosity hydrogel composition according to the present invention (19-0155-101 / F1) was also tested at the same concentration. Figure 9 shows the corresponding skin whitening results for the two formulations. Norepinephrine solution and commercially available MIRVASO® gel (0.5% brimonidine tartrate) are also included for comparison.

[0227] The compositions tested are listed in the table above.

[0228] Modified MIRVASO gel (1.5% brimonidine tartrate 19-0155-0098 / F1) resulted in a substantial increase in the intensity and duration of skin whitening compared to commercially available MIRVASO® gel (0.5% brimonidine tartrate).

[0229] On the other hand, the intensity of skin whitening did not persist for the desired long period of time to solve the technical problems of the present invention.

[0230] Similar to this performance limitation, the MIRVASO vehicle is also unsuitable for radiation dermatitis. As mentioned earlier, the presence of titanium dioxide particles in the MIRVASO vehicle interferes with and disrupts the radiation therapy dose associated with the high-energy electromagnetic waves used.

[0231] Surprisingly, the low-viscosity hydrogel formulation according to the present invention (19-0155-101 / F1) provided improved performance in terms of onset of action, peak effect, and duration of action compared to the modified MIRVASO gel (1.5% brimonidine tartrate 19-0155-0098 / F1).

[0232] The low-viscosity hydrogel formulation according to the present invention (19-0155-101 / F1) demonstrated remarkable superiority in performance 8 hours after application (Figure 9).

[0233] The reproducibility of the skin whitening model was demonstrated by a small standard deviation associated with three replicas of formulation 19-0155-101 / F1 (in Figure 9, the results are presented as the mean ± standard deviation of the three replicas).

[0234] [Example 11] This example is provided to demonstrate the advantages arising from increasing the concentration of xanthan gum in the hydrogel composition according to the present invention. Hydrogel formulation 19-0155.0163 contains 0.5% w / w xanthan gum, while the other formulations tested, 19-0155.0135 / F1 and 19-0155.0111 / F1, contain 0.2% w / w xanthan gum. Details of formulations 19-0155.0135 / F1 and 19-0155.0111 / F1 are shown in Tables 9 and 7, respectively, and formulation 19-0155.0163 is described in detail in Table 12 below.

[0235] [Table 12]

[0236] Table 13 below lists the stability data obtained for formulation 190155.0163.

[0237] [Table 13]

[0238] The composition according to the present invention, which contains a high concentration of xanthan gum (for example, 0.5% compared to 0.2% w / w), was advantageous because the hydrogel was well retained at the application site.

[0239] Generally, increasing the level of thickeners, such as xanthan gum, tends to reduce the transdermal release of activators from topically applied semi-solids.

[0240] However, as shown in Figure 10, the results obtained (average of two replicates) regarding skin whitening scores obtained by comparing hydrogel compositions according to the present invention containing different concentrations of xanthan gum with MIRVASO® products, showed that composition 190155.0163 according to the present invention, containing xanthan gum at a concentration of 0.5%, yielded the best results, comparable to those obtained with similar compositions containing 0.2% xanthan gum.

Claims

1. A composition that is aqueous, suitable for local administration, and contains a vasoconstrictor, wherein the vasoconstrictor is Polyethylene glycol combined with propylene glycol and at least one of dimethyl sulfoxide (DMSO), A hydrophilic film-forming agent selected from polyvinylpyrrolidone / vinyl acetate copolymer and non-crosslinked polyvinylpyrrolidone, Glycerin and It is characterized by being selected from brimonidine or a salt thereof in a solvent system phase containing, A composition characterized in that the composition is in the form of a hydrogel.

2. The composition according to claim 1, characterized in that it contains polyvinylpyrrolidone / vinyl acetate copolymer as a hydrophilic film-forming agent.

3. The composition according to claim 1 or 2, further comprising, alone or in combination, a gel-forming agent selected from xanthan gum and hydroxyethylcellulose (HEC).

4. It is characterized by further containing natural or synthetic antioxidants or free radical scavengers. The composition according to any one of claims 1 to 3.

5. The composition according to claim 4, characterized in that the antioxidant is selected, either alone or in a mixture, from butylated hydroxyanisole (BHA), DL-tocopherol, butylated hydroxytoluene (BHT), propionaldehyde, palmitate, ascorbate, or glutathione.

6. The composition according to claim 4, characterized in that the antioxidant is selected from BHA and / or DL-tocopherol.

7. The composition according to any one of claims 4 to 6, characterized in that the antioxidant is contained in a concentration of 0.1% to 4.0% by weight of the total weight of the composition.

8. The composition according to any one of claims 4 to 6, characterized in that the antioxidant is contained in a concentration of 0.1% to 1.0% by weight of the total weight of the composition.

9. A composition according to any one of claims 4 to 8, characterized by containing an antioxidant and further containing polysorbate and / or polyoxyethylene hydrogenated castor oil 40.

10. The composition according to any one of claims 1 to 9, characterized in that it contains brimonidine or a salt thereof at a concentration of 0.15% to 3.00% by weight of the total weight of the composition.

11. The composition according to any one of claims 1 to 9, characterized in that it contains brimonidine or a salt thereof at a concentration of 0.50% to 2.50% by weight of the total weight of the composition.

12. The composition according to any one of claims 1 to 9, characterized in that it contains brimonidine or a salt thereof at a concentration of 0.75% to 1.50% by weight of the total weight of the composition.

13. The composition according to any one of claims 1 to 9, characterized in that it contains brimonidine or a salt thereof at a concentration of 1.00% or 1.50% by weight of the total weight of the composition.

14. The composition according to any one of claims 1 to 13, characterized in that the brimonidine salt is brimonidine tartrate.

15. The composition according to any one of claims 1 to 14, characterized in that it contains propylene glycol at a concentration of 20% by weight of the total weight of the composition, and polyethylene glycol at a concentration of 10% by weight of the total weight of the composition.

16. The composition according to any one of claims 1 to 15, characterized by comprising oleyl alcohol and vitamin E alone or in combination.

17. A composition according to any one of claims 1 to 16 for use as a pharmaceutical.

18. A composition for use according to claim 17, for the prevention and / or treatment of dermatitis caused by radiation.

19. The composition for use according to claim 17 for the prevention and / or treatment of dermatitis caused by radiation during radiotherapy.

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