Emulsion composition, and its use in the prevention and / or treatment of skin damage caused by radiation.

Abstract

The present invention relates to an aqueous composition in a form suitable for topical administration, comprising a vasoconstrictor.The present invention is characterized in that the composition, in the form of an emulsion containing liquid crystals, comprises a vasoconstrictor selected from brimonidine or a salt thereof, in a solvent system phase comprising polyethylene glycol in combination with propylene glycol, a hydrophilic film former selected from polyvinylpyrrolidone / vinyl acetate copolymer, alone or in combination, and polyvinylpyrrolidone in non-crosslinked, crosslinked or acetate form, an emulsifier selected from a combination of glycerin, PEG-75 stearate and glyceryl monostearate, and a combination of polyoxyethylene-20 sorbitan monostearate (polysorbate-60) and cetostearyl alcohol, oleic acid or oleyl alcohol, preferably oleyl alcohol, and an oil phase suitable for obtaining an emulsion containing liquid crystals.

Description

Technical Field

[0007]

[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 comprising 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 alpha, beta or gamma rays, and radiation consisting of protons.

Background Art

[0003] One of the initial effects of radiation exposure to tissue is erythema, an inflammatory reaction 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. <000***013>

[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 from an immediate reduction in blood flow by decreasing the diameter of arterioles and small blood vessels in the dermis, particularly manifested as a reduction in skin color.

[0005] MIRVASO® Gel (0.5% w / w brimonidine tartrate) is indicated for the symptomatic treatment of facial erythema associated with rosacea in adults.

[0006] Brimonidine is particularly known as a highly selective α2 - adrenergic receptor agonist. Brimonidine has more than 1000 - fold selectivity for the α2 - adrenergic receptor over the α1 - adrenergic receptor.

[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 Application No. 10 / 853585, U.S. Patent Application No. 10 / 626037, and U.S. Patent Application No. 12 / 193098.

[0008] Brimonidine (tartrate) has a solubility profile that offers chemical stability suitable for topical administration and a variety of formulation options.

[0009] For example, the applicant is aware of International Publication No. 2015 / 013709, which describes the reduction and / or suppression of radiation-induced skin hyperplasia by using brimonidine tartrate, for example, by topical administration in emulsion form, at a concentration of 0.01 to 5% by weight, preferably 0.1 to 2% by weight. For example, this document describes a composition comprising an ethyl ester copolymer based on PVM / MA, an alcohol phase consisting of ethanol and dimethicone, an aqueous phase based on PVP / PA copolymer, and an oil phase containing oleth-20, cocamide MEA and steareth-16. Such formulations contain ethanol, which causes itching and burning sensations in patients with skin damage, and are therefore unsuitable, in particular, for the treatment of radiation-induced dermatitis.

[0010] Furthermore, the applicant is aware that U.S. Patent Application Publication No. 2011 / 0224216 describes a method for treating induced erythema, for example, by physical procedures, such as laser radiation, UV radiation, radiofrequency, radiotherapy, light-emitting diodes, or by topical administration of a composition particularly in the form of a cream, which particularly contains brimonidine tartrate, PEG-300, and PEG-6 stearate.

[0011] Furthermore, the applicant is aware that International Publication No. 2012 / 075319 describes an oxymetazoline-based composition for the treatment of rosacea and rosacea-related symptoms, further comprising butylhydroxytoluene, PEG, glycol, PEG-32 stearate, cetostearyl alcohol, and oleyl alcohol.

[0012] Topical products designed for therapeutic purposes typically consist of an active ingredient and excipients. During formulation, the selection of excipients is necessary to ensure drug efficacy by dissolving the active ingredient and optimizing its skin permeability, for the stability and texture of the galenos form, for local tolerance, and for patient compliance. Optimizing each of these individual components, as well as considering complex and complementary issues, leads to identifying the optimal balance of these key factors to provide a product that meets the demands of patients, healthcare professionals, and regulatory bodies.

[0013] On the other hand, ionizing surfactants containing salts do not readily penetrate the stratum corneum (a barrier mainly composed of lipids), making it difficult for them to be released and for skin reservoirs to form. Furthermore, such surfactants tend to be rapidly removed from biological tissues due to their solubility in water.

[0014] In fact, because brimonidine is a hydrophilic molecule, it does not easily pass through the lipid-rich stratum corneum.

[0015] 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 removed, thus reducing its effectiveness in vasoconstriction.

[0016] Therefore, the structure of the barrier 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 rapidly removed by the lower hydrophilic layer after passing through the outer lipid layer.

[0017] Furthermore, the concentration of active vasoconstrictors should not be too high, as this poses a risk of significant and potentially harmful systemic exposure.

[0018] Furthermore, certain compounds used in compositions for topical application may cause side effects, which can limit 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 with the treatment or dissatisfaction with the treatment on the patient's part.

[0019] For this purpose, a formulation of MIRVASO® gel 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.

[0020] 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.

[0021] Radiation dermatitis (or radiation-induced dermatitis) can cause painful and distressing lesions that may lead to temporary or permanent discontinuation of treatment.

[0022] 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.

[0023] For acute grade 1 radiation dermatitis, emollients applied several hours after a radiation session (e.g., DEXERYL® or TOPICREME®) moisturize the skin and provide the patient with a brief period of well-being.

[0024] 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.

[0025] 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.

[0026] 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 preventing the progression of radiation dermatitis, they are effective in cases of local allergic reactions (e.g., dermatitis associated with adhesives used for marking purposes).

[0027] In cases of acute radiation dermatitis, the continuation of radiation therapy may be temporarily interrupted if the radiation therapist deems it necessary or preferable, depending on the progress and priority of the treatment.

[0028] The use of epinephrine as a topical vasoconstrictor for the prevention of radiation dermatitis in breast cancer patients undergoing radiotherapy has been described (James F. Cleary et al., Significant suppression of radiation dermatitis in breast cancer patients using a topically applied adrenergic vasoconstrictor, Radiation Oncology, 2017).

[0029] However, such products are immediate alcohol-based preparations that evaporate and need to be applied from immediately before to up to 20 minutes before treatment with radiotherapy.

[0030] Moreover, most notably, its effectiveness is limited by its overly short duration of action. In the study in question, it showed significant benefits in only 50% of patients.

[0031] In cancer treatment where patients already feel intolerable, side effects may limit the optimal treatment process and may prevent it. Therefore, there is a real 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.

[0032] Thus, there is a need to develop a new formulation aimed at overcoming the above-mentioned drawbacks regarding the tolerance, effectiveness, and compliance of patients receiving radiation, especially cancer patients treated with radiotherapy, by causing a strong and long-term controlled reduction in skin blood flow restricted to the application site over time.

Summary of the Invention

[0033] [Technical Problem] In light of the above circumstances, one of the problems that the present invention aims to solve is to develop an optimized topical formulation based on an established vasoconstrictor, such as brimonidine tartrate, which prevents and significantly reduces the main skin side effects caused by radiation, particularly in the treatment of cancer by radiotherapy, and improves the duration of activity and efficacy of the vasoconstrictor.

[0034] [Benefits you can gain] The applicant has developed novel topical compositions that enable the bioavailability of vasoconstrictors in the dermis and epidermis for 12-14 hours or more, while avoiding interference from radiotherapy rays that may reduce the effectiveness of the treated tumor or irradiation field, thereby improving the duration and efficacy of vasoconstriction by protecting the skin from radiation-induced damage, particularly from side effects of radiotherapy treatment.

[0035] Complex and difficult-to-supply combinations containing low molecular weight (less than 150 g / mol, preferably less than 100 g / mol) polar solvents and higher molecular weight (greater than 150 g / mol, preferably between 350 and 650 g / mol) polar solvents have been developed to form brimonidine tartrate reservoirs on the skin surface and in the upper layers of the stratum corneum. However, reservoir formation of hydrophilic compounds is far more complex than that of lipophilic substances, as 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).

[0036] In addition to the parameters mentioned above, other factors crucial 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.

[0037] 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 reduction in its effectiveness without interfering with the passage of radiation through the skin.

[0038] The composition according to the present invention enables the formation of a reservoir of active polar vasoconstrictors in the stratum corneum, a phenomenon usually achieved only with lipophilic molecules, such as corticosteroids, which are typically quickly "washed out" by the bloodstream. 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 patients and radiotherapists.

[0039] The optimized composition is particularly suitable for radiation therapy, helping to improve patient compliance and maximize the effectiveness of anti-cancer treatments.

[0040] 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.

[0041] Ultimately, the pharmaceutical compositions developed by this invention are also economical, easy to prepare, and can be prepared quickly.

[0042] [Technical solution] The first objective of the solution to the above-mentioned problem is an aqueous composition suitable for topical administration containing a vasoconstrictor, wherein the composition is in the form of an emulsion containing a liquid crystal, preferably in water-in-oil or oil-in-water, more preferably in oil-in-water, and the vasoconstrictor is - Polyethylene glycol combined with propylene glycol; - A hydrophilic film-forming agent selected from polyvinylpyrrolidone / vinyl acetate copolymer alone or in combination, or from polyvinylpyrrolidone (PVP) in non-crosslinked, crosslinked, or acetic acid form, preferably polyvinylpyrrolidone / vinyl acetate copolymer as a hydrophilic film-forming agent; - Glycerin; - Emulsifiers selected from a combination of PEG-75 stearate and glyceryl monostearate, and a combination of polyoxyethylene-20 sorbitan monostearate (polysorbate-60) and cetostearyl alcohol; - Oleic acid or oleyl alcohol, preferably oleyl alcohol; equivalent - An oil phase suitable for obtaining an emulsion containing liquid crystals, preferably a water-in-oil or oil-in-water type, more preferably an oil-in-water type. The composition is a solvent-based phase containing brimonidine or a salt thereof, selected from brimonidine or a salt thereof.

[0043] The second objective is a composition according to the present invention for use as a pharmaceutical.

[0044] 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]

[0045] [Figure 1]This figure shows the stability measurements using LUMiSizer® for composition 19-0155.0045 (W / O emulsion based on Brij® / Arlamol), composition 19-0155.0065P (W / O emulsion based on Brij / Arlamol), composition 19-0155.0090 (W / O emulsion based on Gelot 64), and composition 19-0155.0091 (W / O emulsion based on Polawax). [Figure 2] This figure shows the stability measurements using LUMiSizer® for compositions 19-0155.0044, 19-0155.0070P, 19-0155.0076 / F2, 19-0155.0083, 19-0155.0086, 19-0155.0088, and 19-0155.0089. [Figure 3] Example 5, more specifically, is a diagram illustrating viscosity measurements obtained with various compositions using reference composition 19-0155-0090P / F3 under process conditions as shown in Table 14. [Figure 4] This figure shows skin whitening scores obtained from various W / O emulsion compositions: 19.0155-0083 / F1 (Gelot-64 based), 19.0155-0087 / F1 (Gelot-64 based), and 19.0155.0086A / F1 (Polawax based). [Figure 5] This figure shows the skin whitening scores obtained with various emulsion compositions: 19-0155.0091 / F1 (Polawax-based), 19-0155.0089 / F1 (Brij-based), and 19-0155-0090 / F1 (Gelot-based). [Figure 6] This figure shows skin whitening scores obtained with various active (including brimonidine tartrate) or inactive (including vehicle only) oil-in-water emulsions. [Figure 7]This figure shows the skin whitening scores obtained with various active (containing brimonidine tartrate, 19-0155-0102 / F5) or inactive (containing only the vehicle, 19.0155-0102P / F2) oil-in-water emulsion compositions. [Figure 8] This figure shows the average erythema score obtained from various active (containing brimonidine tartrate) or inactive (containing only the vehicle) oil-in-water emulsion compositions. [Figure 9] This figure shows the skin whitening score obtained by referencing vasoconstrictor products. [Figure 10] This figure shows the skin whitening score obtained using a modified MIRVASO composition containing 1.5% w / w brimonidine tartrate (19-0155-0098 / F1), norepinephrine solution, and MIRVASO® (0.5% w / w brimonidine tartrate). [Modes for carrying out the invention]

[0046] The present invention relates to an aqueous composition containing a vasoconstrictor in a form suitable for topical administration.

[0047] The local composition according to the present invention is characterized in that it is in the form of an emulsion having liquid crystals, preferably in the form of a water-in-oil or oil-in-water type, more preferably in the form of an oil-in-water type.

[0048] Liquid crystals are an infinite collection of molecules that greatly improve solubility and facilitate emulsification.

[0049] From a microstructural perspective, the combination of hydrophilic nonionic emulsifiers and aliphatic alcohols induces specific organization in the continuous phase of the emulsion by producing liquid crystals surrounded by lamellar phases. The extent of the lamellar phase is related to the excess aliphatic alcohol.

[0050] Liquid crystal formulations offer several advantages as vehicles for topical compositions, and these advantages include: - Repair of the skin barrier; - Delivery of moisture to the skin; - Excellent resistance; - Improved skin release of certain activators, Includes.

[0051] The topical compositions according to the present invention are - Polyethylene glycol combined with propylene glycol; - A hydrophilic film-forming agent selected from polyvinylpyrrolidone / vinyl acetate copolymer (KOLLIDON VA 64®), either alone or in combination with polyvinylpyrrolidone (PVP) in non-crosslinked, crosslinked, or acetic acid form, preferably polyvinylpyrrolidone / vinyl acetate copolymer as a hydrophilic film-forming agent; - Glycerin; - Emulsifiers selected from a combination of PEG-75 stearate and glyceryl monostearate, and a combination of polyoxyethylene-20 sorbitan monostearate (polysorbate-60) and cetostearyl alcohol; - Oleic acid or oleyl alcohol, preferably oleyl alcohol; equivalent - An oil phase suitable for obtaining an emulsion containing liquid crystals, preferably a water-in-oil or oil-in-water type, more preferably an oil-in-water type; The solvent phase contains a vasoconstrictor selected from brimonidine or a salt thereof.

[0052] "Salt or pharmaceutically acceptable salt" refers to salts of a compound of interest that are safe and effective for topical use in mammals and possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in a particular compound. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, hydrobroms, hydroiodides, nitrates, sulfates, bisulfates, phosphates, superphosphates, isonicotinates, acetates, lactates, salicylates, citrates, tartrates, pantothenates, hydrogen tartrates, ascorbic acidates, succinates, maleates, gentisinates, fumarates, glucons, glucurons, sugarates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, benzenesulfons, p-toluenesulfons, and pamoates (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoates)). Certain compounds used in this invention can form pharmaceutically acceptable salts with various amino acids. Suitable basic salts include, but are not limited to, aluminum salts, calcium salts, lithium salts, magnesium salts, potassium salts, sodium salts, zinc salts, and diethanolamine salts. For a general overview 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 comprising stoichiometric or non-stoichiometric amounts of water bound thereto by non-covalent intermolecular forces.

[0053] Preferably, the brimonidine used in the composition according to the present invention is brimonidine tartrate; however, the salt form presents problems in terms of the stability of water-in-oil or oil-in-water emulsion formulations.

[0054] 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 is advantageous for the design and evaluation of aqueous formulations and can provide improved performance in terms of sensory and topical tolerance.

[0055] 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.

[0056] 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% w / w and 1.50% w / w, more preferably between 1.00% w / w and 1.50% w / w, and even more preferably between 1.00% w / w or 1.50% w / w.

[0057] The concentration of brimonidine, preferably brimonidine tartrate, and the dose applied can be advantageously adapted according to the application site.

[0058] In fact, the barrier formed by the skin, particularly the stratum corneum through which the stratum corneum is penetrated, is thicker on the hands and feet than on the scalp, and is of moderate thickness on other parts of the body, especially the chest. Therefore, the concentration preferably used for the same dose is advantageously lower on the scalp, for example, in the range of 0.15 to 0.5% w / w, compared to the concentrations used on other parts of the body, for example, 0.75 to 1.5% w / w on the chest, or for example, 1.5 to 3% w / w on the hands and feet.

[0059] Preferably, the oil phase of a water-in-oil or oil-in-water emulsion comprising liquid crystal according to the present invention comprises, alone or in combination, cetyl alcohol and stearyl alcohol, and / or, alone or in combination, triglyceride esters of saturated caprylic and saturated caprin fatty acids of coconut / palm kernel and plant-derived glycerol (Miglyon 812N), and stearyl ether of polypropylene glycol (PPG)-11 (Arlamol PS11E-LQ-[RB]).

[0060] Preferably, the oil phase contains a combination of cetyl alcohol and stearyl alcohol.

[0061] The oil phase of the water-in-oil or oil-in-water emulsion composition containing liquid crystal according to the present invention preferably contains a combination of cetyl alcohol, stearyl alcohol, and oleyl alcohol at a concentration between 1% by weight and 15% by weight of the total weight of the composition, preferably between 2.5% w / w and 10% w / w.

[0062] Preferably, the oil phase comprises a combination of triglyceride esters of caprylic and caprin fatty acids saturated with coconut / palm kernel and plant-derived glycerol, and stearyl ether of PPG-11.

[0063] The oil phase of the water-in-oil or oil-in-water emulsion composition containing liquid crystal according to the present invention preferably contains a combination of caprylic and caprin fatty acids saturated with coconut / palm kernel triglyceride esters of plant-derived glycerol and stearyl ether of PPG-11 at a concentration of 5% to 10% by weight of the total weight of the composition.

[0064] The topical composition according to the present invention is characterized by containing polyethylene glycol (PEG) in combination with propylene glycol (PG).

[0065] 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.

[0066] This is primarily due to its high polarity and molecular weight, which limit absorption into 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.

[0067] Furthermore, PEG's high solubilizing ability can provide near-optimal thermodynamics for topical administration, and when used at high concentrations, it cannot be used to promote product transformation, often associated with the evaporation of volatile components such as water, in order to facilitate 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 through contact migration.

[0068] Improved 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.

[0069] The permeability and penetration of PEG have also been shown to depend on its molecular weight.

[0070] Nevertheless, in the water-in-oil or oil-in-water emulsion composition according to the present invention, PEG is necessary for topical formulation.

[0071] 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 favorably contributes to the stability and tolerance of the water-in-oil or oil-in-water emulsion composition according to the present invention by limiting the potential for irritation, removing polar impurities, and consequently reducing the interaction between the excipient and the activator (brimonidine tartrate) and the subsequent degradation of the activator.

[0072] 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 vascular system of the reticular tissue where the target site of brimonidine tartrate is located. PEG-400 or PEG-400SR has sufficient solubility to promote better retention of brimonidine tartrate in solution on the skin surface and in the upper layers of the stratum corneum.

[0073] Preferably, the composition according to the present invention contains PEG at a concentration between 1% and 20% by weight, preferably between 5% and 15% by weight, and more preferably between 10% by weight, of the total weight of the composition.

[0074] 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.

[0075] 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 topical anesthetics.

[0076] On the other hand, in the case of brimonidine tartrate, PG exhibits 50% of the solubilizing capacity of glycerin.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] Thus, PG has favorable physical and chemical properties with respect to skin permeability and absorption 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 resistance mechanisms.

[0081] 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.

[0082] For an even stronger reason, PG is known to penetrate the skin more rapidly than activators, and therefore the precipitation of activators on the skin surface limits the duration of their action.

[0083] 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.

[0084] In the topical compositions according to the present invention, the choice to use PG as the solvent and penetration enhancer is not easily predictable based on solubility and other vehicle-related variables.

[0085] 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.

[0086] In the water-in-oil or oil-in-water emulsion composition according to the present invention, controlling the PEG:PG ratio offers particular advantages.

[0087] Excessively high concentrations of PEG, especially those exceeding 50% w / w, when combined with PG, have a negative impact on the vasoconstrictive intensity of brimonidine tartrate.

[0088] In one preferred embodiment, PEG and PG are used in a ratio of 1:1 to 1:5, preferably 1:2.

[0089] 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.

[0090] The topical compositions according to the present invention are characterized by comprising, alone or in combination, a hydrophilic film-forming agent selected from non-crosslinked, crosslinked, or acetic acid-formed polyvinylpyrrolidone / vinyl acetate copolymer (PVP).

[0091] Preferably, the composition according to the present invention comprises, 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, based on the total weight of the composition.

[0092] Preferably, the topical composition according to the present invention contains polyvinylpyrrolidone / vinyl acetate copolymer (KOLLIDON VA 64®) as a hydrophilic film-forming agent.

[0093] Preferably, the composition according to the present invention contains polyvinylpyrrolidone / vinyl acetate copolymer (KOLLIDON VA 64®) at a concentration between 0.1% and 1.5% by weight of the total weight of the composition, preferably between 0.25% and 1.4% by weight, more preferably between 0.5% and 1.3% by weight, even more preferably between 0.75% and 1.25% by weight, and even more preferably between 1% by weight.

[0094] The topical composition according to the present invention is characterized by further comprising glycerin.

[0095] Glycerin (glycerol) is known as a moisturizer that can improve moisture retention in the stratum corneum and enhance hydration.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] Preferably, the composition according to the present invention contains glycerin at a concentration between 1% and 20% by weight of the total weight of the composition, preferably between 2% and 15% by weight, more preferably between 3% and 10% by weight, and even more preferably between 4% by weight.

[0100] In a particularly advantageous manner, the combination of PG and glycerin improves the distribution of the activator, preferably brimonidine tartrate, in the stratum corneum.

[0101] The topical composition according to the present invention is characterized by further comprising an emulsifier selected from a combination of PEG-75 stearate and glyceryl monostearate, and a combination of polyoxyethylene-20 sorbitan monostearate (polysorbate-60) and cetostearyl alcohol, preferably a combination of PEG-75 stearate and glyceryl monostearate (Gelot 64).

[0102] According to one preferred embodiment, the composition according to the present invention comprises a combination of PEG-75 stearate and glyceryl monostearate (Gelot 64), which contains an aliphatic component having a melting point between 46 and 66°C.

[0103] Considering the manufacturing process, the most crucial step after emulsification, which takes place at a temperature of approximately 65±5°C, is the cooling stage. The decrease in temperature causes the aliphatic components to crystallize when they reach their transition temperature.

[0104] During the cooling phase, aliphatic emulsifiers / auxiliary emulsifiers organize around the oil droplets. Lipophilic auxiliary emulsifiers mainly remain within the oil droplets, while hydrophilic emulsifiers and amphiphilic aliphatic alcohols remain at the interface between the emulsion's oil droplets and the continuous aqueous phase.

[0105] Preferably, the composition according to the present invention contains an emulsifier, such as GELOT 64®, at a concentration of 1% to 10% by weight of the total weight of the composition, preferably 2% to 7% by weight, more preferably 3% to 5% by weight, and even more preferably 3% w / w, or contains POLAWAX® at a concentration of 3% to 15% by weight of the total weight of the composition, preferably 5% to 12% by weight, and more preferably 10% w / w.

[0106] The topical composition according to the present invention is characterized by further comprising oleic acid or oleyl alcohol, preferably oleyl alcohol (KOLLICREAM OA®).

[0107] Preferably, the composition according to the present invention contains oleic acid or oleyl alcohol at a concentration of 0.1% to 7% by weight, preferably 1% to 5% by weight, and more preferably 2.5% by weight, of the total weight of the composition.

[0108] Preferably, the topical composition according to the present invention further comprises xanthan gum as a gelling agent.

[0109] Preferably, the composition according to the present invention contains xanthan gum at a concentration between 0.1% and 1.5% by weight of the total weight of the composition, preferably between 0.2% and 1% by weight, and more preferably between 0.2% and 0.5% by weight.

[0110] A soft mixed film is favorably formed on the skin surface using other non-volatile solvents, PG and PEG, as well as xanthan gum and / or HEC, and 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.

[0111] Preferably, the topical composition according to the present invention further comprises a natural or synthetic antioxidant or a free radical scavenger.

[0112] The antioxidant is preferably selected from butylated hydroxyanisole (BHA), DL-tocopherol, butylated hydroxytoluene (BHT), propionaldehyde, ascorbate, palmitate, or glutathione, either alone or in a mixture, preferably in a mixture, and is preferably selected from BHA and / or DL-tocopherol.

[0113] In the water-in-oil or oil-in-water emulsion composition according to the present invention, the antioxidant is used in an amount between 0.01% and 4.0% by weight of the total weight of the composition, more preferably between 0.1% and 1.0% by weight, and even more preferably at 0.1% by weight. For example, BHA is preferably used at a concentration of 0.1% w / w and / or DL-tocopherol at 0.1% w / w.

[0114] Preferably, the topical composition according to the present invention further comprises, alone or in combination, a paraben selected from methylparaben, propylparaben, or isopropylparaben.

[0115] Preferably, the compositions according to the present invention contain parabens, either alone or in combination, at a concentration between 0.01% and 0.5% by weight, preferably between 0.1% and 0.4% by weight, and more preferably between 0.3% by weight, of the total weight of the composition.

[0116] Preferably, the composition according to the present invention further comprises phenoxyethanol, preferably at a concentration between 0.15% and 1.5%, more preferably between 0.4% and 1.25%, even more preferably between 0.5% and 1.1%, and even more preferably at a concentration of 1% w / w; sodium benzoate, preferably at a concentration between 0.05% and 0.5%, more preferably between 0.1% and 0.3%, and even more preferably at a concentration of 0.2% w / w; phenylethyl alcohol as an alternative preservative, preferably at a concentration between 0.1% and 1%, more preferably between 0.25% and 0.75%, and even more preferably at a concentration of 0.5% w / w; and / or EDTA as a chelating agent to aid in the preservation and stability of the composition, preferably at a concentration of 0.2% w / w.

[0117] More preferably, the composition comprises a combination of phenoxyethanol, sodium benzoate, phenylethyl alcohol, and EDTA.

[0118] 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.

[0119] The incorporation of antioxidants beneficially improves the stability of the surfactant and oil phase.

[0120] Furthermore, the oil phase used was selected to facilitate emulsion formation, physical stability, and the achievement of the desired microstructure, while also aiding skin delivery and exhibiting appropriate sensory performance.

[0121] Therefore, the water-in-oil or oil-in-water emulsion compositions according to the present invention improve and extend the transdermal delivery of brimonidine tartrate, enabling the meeting of patient needs through sufficient long-lasting local vasoconstriction and excellent protection of the epidermis and dermis from oxygen-reactive and inflammatory mediators.

[0122] The compositions according to the present invention are easy to apply and can be applied to potentially irritated skin.

[0123] These dry quickly, leaving only a very small residue on the skin.

[0124] The topical composition according to the present invention has a pH between 3.5.0 and 6.5, preferably between 4.0 and 5.5, and more preferably 4.5.

[0125] The water-in-oil or oil-in-water emulsion compositions according to the present invention are designed to contain relatively large amounts of glycol, such as 20% PG and 10% PEG-400. These relatively high concentrations of components may disrupt the interface and make emulsifiers and auxiliary emulsifiers soluble, thus not necessarily supporting the stability and maintenance of the microstructure. Furthermore, the addition of brimonidine tartrate, an active salt, at relatively high concentrations may physically destabilize the interface and the emulsion.

[0126] However, these properties make it possible to obtain water-in-oil or oil-in-water, preferably oil-in-water, emulsion compositions that have a high density of small oil droplets and liquid crystals, improving the surface area of ​​these structures and promoting the permeation of the activator into the stratum corneum.

[0127] Another object of the present invention relates to a water-in-oil or oil-in-water, preferably oil-in-water, emulsion composition according to the present invention for use as a pharmaceutical.

[0128] Preferably, the water-in-oil or oil-in-water emulsion compositions according to the present invention are 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.

[0129] Preferably, the water-in-oil or oil-in-water emulsion compositions according to the present invention are used particularly for the prevention and / or treatment of dermatitis caused by radiation, such as X-rays, in radiotherapy. [Examples]

[0130] The present invention is demonstrated herein by the following embodiments.

[0131] [Example 1] Measurement of saturation solubility in pure solvent (method) A saturation method was prepared by adding excess pharmaceutical substances to various solvents and storing the samples in sealed containers at room temperature for 24 hours while continuously stirring.

[0132] 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.

[0133] After equilibration time, the sample was centrifuged or filtered, and brimonidine tartrate was quantified using a Thermo Scientific Dionex U3000 UPLC-UV system. The chromatographic 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

[0134] (result) Table 1 below summarizes the saturation solubility results for each solvent used separately.

[0135] [Table 1]

[0136] (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.

[0137] Water is considered the next best solvent, and the salt form of the activator likely works to its advantage in terms of solubility in water.

[0138] Next, in descending order, were glycerin (GLY), glucam, propylene glycol (PG), and PEG-400.

[0139] The solubility observed for other solvents was remarkably low, and the results for the solubility of brimonidine tartrate were not satisfactory.

[0140] Interestingly, well-known solvents, such as Transcutol and DMI, appear to be far less effective than glycerin or propylene glycol against brimonidine tartrate.

[0141] [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.

[0142] (result) Table 2 below summarizes the saturation solubility results for various solvent mixtures.

[0143] [Table 2]

[0144] (Conclusion) As expected, non-aqueous solvent mixtures are thought to have lower solubility power than mixtures containing water.

[0145] Nevertheless, the results 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 / PEG400 / GLY / PVP / water (20:10:5:1:40). This indicates that even after the water evaporates, the non-volatile polar components of the aqueous gel in the residual formulation may have some ability to dissolve brimonidine tartrate on the skin surface and in the stratum corneum.

[0146] 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.

[0147] 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.

[0148] [Example 3] Measurement of stability in a single solvent and a preliminary mixture of solvents The solvent combinations were prepared as shown in Table 3 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.

[0149] [Table 3]

[0150] Table 4 below summarizes the compatibility data generated in this study.

[0151] [Table 4]

[0152] The results showed that the mean was between 99.36% and 101.45%, and the relative standard deviation was less than 1%.

[0153] The solvent mixture without Glucam E20 showed the most favorable stability profile.

[0154] Solvent mixtures without Glucam E20 exhibited 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 with M8 (water, 30% Transcutol), followed by M1 (water, 10% DMSO, 5% Glucam E10, and 5% glycerin).

[0155] The data obtained showed that using Glucam E10 and E20 increased the risk of instability in brimonidine tartrate. On the other hand, transcutol, DMSO, and glycerin showed acceptable compatibility profiles.

[0156] [Example 4] Evaluation of the stability of various emulsion compositions using LUMiSizer® technology Various compositions were prepared, and their short-term physical stability was evaluated.

[0157] By using centrifugation and LUMiSizer®, a more quantitative and rapid screening tool, we maximized efficiency and facilitated the screening of various compositions.

[0158] For characterizing and optimizing distribution stability, shelf life, and particle-particle interactions, particle and fragment compressibility, structural stability, and the elastic behavior of deposits and gels, multi-sample LUMiSizer® was ideal.

[0159] The demixing phenomenon was quantified in terms of purification rate and instability index, sedimentation rate and particle suspension rate, remaining turbidity, volume of the separated phase (liquid or solid), and consolidation or dewatering of the sediment.

[0160] The stability of the compositions listed in Tables 5-8 below was evaluated using the standard LUMiSizer® protocol, which includes a 3-hour duration, a temperature of 40°C, and centrifugation at 4000 rpm.

[0161] [Table 5]

[0162] [Table 6]

[0163] [Table 7]

[0164] [Table 8]

[0165] Figure 1 shows the results obtained using LUMiSizer®.

[0166] These preliminary results indicated that formulation 19-0155.0045 (a Brij / Arlamol-based oil-in-water emulsion) was the most unstable, and less stable than the equivalent composition containing only the vehicle (without the activator brimonidine tartrate) (19-0155.0065P).

[0167] The data indicates that the active substance, brimonidine tartrate, has an unstable effect, possibly due to its saline form in this composition.

[0168] On the other hand, other compositions containing the active substance prepared from Gelot 64 (19-0155.0090) and Polawax (19-0155.0091) surprisingly showed similar physical stability to the composition of vehicle 19-0155.0065P.

[0169] Similarly, complementary analyses were performed on the other compositions shown in Tables 9-11 below using LUMiSizer® technology.

[0170] [Table 9] JPEG0007881199000010.jpg73170

[0171] [Table 10]

[0172] [Table 11]

[0173] Figure 2 shows the further results obtained.

[0174] Conventional visual observations and results obtained using Lumisizer® suggest that the Polawax-based composition is the most unstable, and that phase separation was observed after 3 months at 40°C.

[0175] Useful observations were made from the BRIJ / ARLAMOL-based composition.

[0176] The vehicle (19-0155.0070P / F1) was more stable than a similar composition (19-0155.CR2.0044A / F1) containing the activator brimonidine tartrate.

[0177] The addition of 10% w / w PEG-400 improved the stability of all test compositions containing the activator (19-0155.0076 / F2 and 19-0155.0089 / F1 vs. 19-0155.CR2.0044A / F1).

[0178] Stability was also improved by the addition of xanthan gum, with composition 19-0155.0089 / F1 being slightly more stable than composition 19-0155.0076 / F2 (which showed leachate and a slightly higher instability index after 3 months of storage at 40°C).

[0179] Two Gelot 64-based emulsions (19-0155-0083 / F1 and 19-0155-0087 / F1) showed good stability and the best results, even without the beneficial inclusion of xanthan gum as a stabilizer.

[0180] Using the compositions listed in Table 12 below, and as a reference, a Gelot 64-based composition (19-0155.0087 / F1) was also used to test the addition of polymers in a similar additional analysis.

[0181] [Table 12] JPEG0007881199000014.jpg68170

[0182] Further results showed that the stability of emulsion 19-0155.0103 / F1 was dramatically improved by the addition of xanthan gum (0.2% w / w) compared to the reference formulation 19-0155.0087 / F1.

[0183] On the other hand, the inclusion of ingredients, such as SEPINEO P600 (registered trademark), destabilized emulsion 19-0155.0104 / F1, resulting in significantly lower stability compared to the reference formulation 19-0155.0087 / F1.

[0184] [Example 5] Evaluation of the effects of changing various process steps in the production of oil-in-water emulsion compositions Using the vehicles listed in Table 13 below, the effects of various manufacturing process changes on the composition were evaluated in terms of appearance and stability. The initial characteristics of the vehicles in terms of appearance, pH, and viscosity are also described in the table.

[0185] [Table 13]

[0186] Table 14 below shows the results obtained for various process changes.

[0187] [Table 14]

[0188] Figure 3 shows the results regarding viscosity.

[0189] In particular, the "Defloculator" and "Croda" processes described below were compared and tested.

[0190] The "Deflocculator" process used a deglutinating or distributing blade, while the "Croda" process used a paddle stirrer throughout the manufacturing process.

[0191] ("Defloculator" process) (Phase A) Equipment used: Beaker: 600 ml; Type of stirring: Disintegration or distribution blade

[0192] Step 1: Measure and add water, PG, and PEG-400 to a beaker. Heat to 70°C and mix until uniform using a gelatinizer or distribution blade.

[0193] Step 2: Add KOLLIDON to the mixture obtained in Step 1 by weighing it out. Mix until homogeneous using a disintegrating or distribution blade.

[0194] Step 3: Add xanthan gum, which has been pre-distributed in glycerin, to the mixture obtained in Step 2.

[0195] Step 4: Once the contents of the mixture obtained in Step 3 are uniform, measure and add methylparaben.

[0196] Step 5: Within 20 minutes before emulsification, introduce phenoxyethanol into the mixture obtained in Step 4.

[0197] (Phase B) Equipment used: Another beaker; Type of stirring: Magnetic bar

[0198] Step 6: Measure and add all excipients that make up the aliphatic phase. Heat to 70°C and mix until uniform.

[0199] (Emulsification phase) Type of agitation: Disintegration or distribution blade

[0200] Step 7: Pour the Phase B mixture obtained in Step 6 into the Phase A mixture obtained in Step 5, while mixing at 70°C and 500 rpm for 10 minutes.

[0201] (cooling process) Type of agitation: Disintegration or distribution blade

[0202] Step 8: Remove the mixture obtained in Step 7 from the hot plate and allow it to cool to 35°C while stirring at 200-300 rpm.

[0203] Step 9: Between 30°C and 35°C, the viscosity of the formulation increases, and the product is removed from the beaker walls using a spatula.

[0204] Step 10: Once the mixture obtained in Step 9 is homogeneous, adjust the pH to approximately 4.5-5 using a 10% citric acid solution.

[0205] Step 11: After adjusting the pH, mix using a disintegrating / distributing blade at approximately 200 rpm for 20 minutes.

[0206] Step 12: After completing Step 11, finish with water (qs).

[0207] ("Croda" process) (Phase A) Equipment used: Beaker: 600ml; Type of stirring: Paddle stirrer

[0208] Step 1: Measure and add water and methylparaben to a beaker. Heat to 70°C and stir with a paddle stirrer until uniform.

[0209] Step 2: Add KOLLIDON to the mixture obtained in Step 1 by measuring it. Mix with a paddle shaker until uniform.

[0210] Step 3: At 65°C, xanthan gum, which has been pre-distributed in glycerin, is added to the mixture obtained in Step 2.

[0211] (Phase B) Equipment used: Another beaker; Type of stirring: Magnetic bar

[0212] Step 4: Measure and add all excipients that make up the aliphatic phase. Heat to 70°C and mix until uniform.

[0213] (Emulsification phase) Type of stirring: Ultra Turrax

[0214] Step 5: Pour the Phase B mixture obtained in Step 4 into the Phase A mixture obtained in Step 3, while mixing at 70°C and 11,500 rpm for 2 minutes.

[0215] (cooling process) Type of stirring: Paddle stirrer (with holes)

[0216] Step 6: Remove the mixture obtained in Step 5 from the hot plate and allow it to cool to 35°C while stirring at 200-300 rpm.

[0217] Step 7: While cooling, introduce PG and PEG-400 into the mixture obtained in Step 6.

[0218] Step 8: At 35°C to 40°C, add phenoxyethanol to the mixture obtained in Step 7 by weighing.

[0219] Step 9: At approximately 30°C, the viscosity of the formulation increases, and the product is removed from the beaker walls using a spatula.

[0220] Step 10: Once the mixture obtained in Step 9 is homogeneous, adjust the pH to approximately 4.5-5 using a 10% citric acid solution.

[0221] Step 11: After adjusting the pH, mix using a paddle shaker at approximately 200 rpm for 30 minutes.

[0222] Step 12: After completing Step 11, finish with water (qs).

[0223] The best results were obtained with the reference formulation using the "deflocculator" process.

[0224] For formulation 19-0155-0090P / F3, this process yielded a monodistributed liquid crystal / lamellar gel phase with appropriate viscosity and high density.

[0225] Due to the small size and high density of the droplets and liquid crystal / lamellar gel phases, the microstructures obtained under these conditions were most effective for drug delivery.

[0226] Such microstructures maximize the specific surface area of ​​the liquid crystal / lamellar gel phase, facilitating the delivery of activators to the skin and improving vasoconstriction in terms of both the intensity and long-term duration of vasoconstriction.

[0227] Therefore, droplet size was influenced by the process used, and the "Croda" process tended to produce significantly smaller droplet sizes than the "Deflocculator" process. This is likely due to the use of a high-shear mixer during the emulsification process and the subsequent use of a paddle stirrer.

[0228] We also identified the cooling rate as an important variable, and found that atmospheric cooling produced the most satisfactory results among the tests conducted.

[0229] Therefore, this experiment allowed us to make several other observations.

[0230] Phenoxyethanol should preferably be introduced after the emulsification step.

[0231] If the active phase (containing the activator) is introduced after emulsification, it must not be heated.

[0232] The microstructure was significantly affected by glycol removal, and the droplet size and liquid crystal / lamellar gel phase size were altered by the "deflocculator" and "Croda" processes.

[0233] The inclusion of 1% w / w dimethicone in the "deflocculator" process (Formulation 0090P / F10) is thought to eliminate the soaping / whitening effect observed when the formulation is applied.

[0234] The microstructure is unlikely to be significantly affected by this small change in dosage form when manufactured using a deflocculator process.

[0235] [Example 6] Evaluation of skin whitening effects of various compositions using an in vivo vasoconstriction model Each composition was tested three times using the in vivo vasoconstriction protocol described below.

[0236] 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.

[0237] After application, a 30-second massage was followed, and then the applied product was allowed to dry for 10 minutes.

[0238] 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.

[0239] Two Gelot 64-based emulsions (Table 10 above) and one Polawax NF-based emulsion (Table 11 above) were evaluated.

[0240] Figure 4 shows the results of skin whitening.

[0241] Similar effects were observed in all emulsions tested.

[0242] Polawax NF emulsion (19-0155,0086A / F1) produced a slightly better overall profile than the Gelot 64-based compositions (19-0155-0083 / F1 and 19-0155-0087 / F1). It should be noted that composition 19-0155,0086A / F1 also contains oleyl alcohol (KOLLICREAM OA, 2.5%) and KOLLIDON VA-64, both of which improve and extend the transdermal delivery of topically applied activators.

[0243] Composition 19-0155-0083 / F1, based on Gelot 64, contains neither polymer nor oleyl alcohol, while composition 19-0155-0087 / F1, also based on Gelot 64, contains KOLLIDON VA-64 and oleyl alcohol. Both Gelot 64-based compositions exhibited superior physical stability compared to the Polawax-based formulations.

[0244] Based on these results, it is considered that the combination of adding oleyl alcohol to xanthan gum and KOLLIDON VA 64 improves the transdermal administration of the active agent while providing the required physical stability.

[0245] Therefore, such oil-in-water emulsions showed improved performance characteristics from the viewpoints of the appearance, intensity, and duration of skin whitening.

[0246] [Example 7] Evaluation of skin whitening effects of various compositions using an in vivo vasoconstriction model Various formulations were tested and the results were divided into two groups: O / W emulsions [oil-in-water] (Gelot 64, Table 14) and O / W emulsions (Polawax, Table 15). All the formulations tested contained xanthan gum, which has advantages from the viewpoint of stability.

[0247] [Table 15]

[0248] [Table 16]

[0249] Figure 5 shows the skin whitening results of W / O emulsions (Polawax, Brij, and Gelot origin) based on the average of three repetitions.

[0250] The Polawax emulsion (19 - 0155.0091 / F1) achieved the highest skin whitening score of 3 between 4 and 10 hours. For the Gelot emulsion (19.0155 - 0090 / F1), a similar but slightly lower intensity profile was observed.

[0251] The Brij-based composition showed some instability (despite the presence of 0.2% xanthan gum) and was considered unsatisfactory.

[0252] [Example 8] Evaluation of skin whitening effects of various compositions using an in vivo vasoconstriction model Tables 17 and 18 below describe the composition and physical stability data for the Gelot 64 and Polawax-based emulsions that were tested.

[0253] [Table 17]

[0254] [Table 18]

[0255] The Gelot-based compositions used are optimized versions of Gelot 64 emulsions (19-0155-0090 / F1 and 19.0155-0103 / F1), while the Polawax emulsion is an optimized variant of Polawax emulsion (19-0155.0091 / F1).

[0256] Each composition was tested three times using the in vivo vasoconstriction protocol described above.

[0257] Figure 6 shows the results obtained. The results showed that formulations containing 1.5% w / w brimonidine tartrate produced high levels of long-term skin whitening, which is indicative of vasoconstriction.

[0258] The tested Gelot-based emulsion achieved maximum whitening performance, slightly lower than the Polawax 19-0155-0133 / F1-based emulsion. This formulation contains the same concentration of activator as the other tested compositions and other active Polawax formulations (19-0155-0132 / F2). The only difference is that composition 19-0155-0133 / F1 contains 1.0% w / w tocopherol, while 19-0155-0132 / F2 contains 0.1% w / w tocopherol.

[0259] Emulsion formulations based on Gelot 64 (19-0155-0102 / F5) and Polawax (19-0155-0132 / F2) yielded similar vasoconstriction profiles. The degree of vasoconstriction was also similar, starting at approximately 1–1.5 after application 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 at 24 hours.

[0260] Figure 7 shows, as an example, the mean skin whitening profile ± standard deviation of the active formulation 19-0155-0102 / F5 and the corresponding vehicle 19-0155-0102P / F2, demonstrating the excellent reproducibility of the vasoconstriction test.

[0261] [Example 9] Evaluation of effectiveness in a UV-induced erythema model The active compositions containing brimonidine tartrate and vehicle, as listed in Table 19 below, were evaluated using a UV-induced erythema model.

[0262] 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.

[0263] The individual minimum erythematous dose (MED) for each subject was determined 24 hours prior to the experiment. Nine small areas were marked on the dorsal torso of each subject, and the composition was applied to these areas at a dose of 5 mg / cm². UV doses were administered at 1 × MED, 2 × MEDs (2 MEDs), and 3 × MEDs (3 MEDs) to be equivalent to these doses.

[0264] Experimental readings were performed 24 hours after irradiation using investigator erythema scores and a chromameter.

[0265] [Table 19]

[0266] Figure 8 summarizes the average erythema score for each composition.

[0267] The active composition containing 1.5% brimonidine tartrate showed a substantial reduction in the erythema score compared to the vehicle. Further advantages regarding the anti-erythema effect were observed when 1.5% w / w brimonidine tartrate was combined with antioxidants. As antioxidant models, BHA and α-tocopherol were used at concentrations of 0.1% w / w and 1% w / w. The formulations containing 1% BHA or 1% α-tocopherol showed the most potent anti-erythema effect and efficiently prevented 2 MEDs. Formulation 19-0155.0102 / F5 (liquid crystal emulsion O / W Gelot 64) produced the most potent anti-erythema effect.

[0268] [Example 10] Performance of the reference product on a skin whitening model A skin blanching (vasoconstriction) model was tested using reference agents known to cause skin blanching / vasoconstriction. The initial studies were conducted using the following, as used by Fahl (Effect of topical vasoconstrictor exposure upon tumoricidal radiotherapy. Int J Cancer;135(4):981~988, 2014) and similar to the formulations used by Cleary et al. (Significant suppression of radiation dermatitis in breast cancer patients using a topically applied adregernic vasoconstrictor. Radiation Oncology, 2017). · MIRVASO® Gel (0.5% w / w brimonidine tartrate) · Clobetasol propionate cream, 0.05% w / w · Noradrenaline hydrochloride solution (in 70:30 ethanol:water, 82 mg / ml)

[0269] The skin blanching model enables the differentiation of skin blanching performance caused by several active agents applied in various formulations, from the perspective of the expression, intensity, and duration of skin blanching.

[0270] This model possesses sufficient reproducibility and discriminatory capabilities for the formulation screening stage.

[0271] Clobetasol propionate cream was selected as a product / activator with a clearly defined effect on skin whitening. In fact, this vasoconstrictive effect has been used to evaluate the efficacy and in vivo bioequivalence of topical corticosteroids (1997 FDA guidance, https: / / www.fda.gov / media / 70931 / download).

[0272] Figure 9 illustrates the skin whitening data for MIRVASO® gel, clobetasol propionate cream, 0.05% w / w, and epinephrine hydrochloride solution (70:30 ethanol:water, 82 mg / ml).

[0273] MIRVASO® gel did not cause significant whitening. This was expected, given that it is designed for application to the relatively thin and sensitive facial skin during rosacea treatment. As a general rule, these products do not contain substances that could penetrate the skin at high concentrations, due to the sensitivity of rosacea patients' skin. Furthermore, facial skin is thinner than chest skin, resulting in a lower barrier to skin penetration and absorption. The strength and duration of action are insufficient to meet the requirements of desired radiation-induced dermatitis treatment.

[0274] Norepinephrine (noradrenaline) solution produced rapid, intermediate skin whitening within one hour of application. However, the effect began to disappear after a 4-hour observation interval. Whitening was less than 0.5 after 10 hours and returned to the initial observation point after only 16 hours. While the initial effect was expected, the duration and intensity of the effect were not sufficient.

[0275] In contrast to the polar norepinephrine molecule and its aqueous ethanol vehicle, clobetasol propionate cream showed a slow onset of action, gradually increasing from 2 hours to a peak whitening score of 2.0 between 14 and 16 hours. From 16 hours, whitening rapidly decreased, returning to the starting point at 24 hours. The slower onset of whitening with clobetasol may be related to the physicochemical characteristics of the activator, where its lipophilic nature leads to reservoir formation and a more restricted distribution in viable epidermis compared to the more hydrophilic norepinephrine. It is also important to note that the pharmacodynamic mechanisms of vasoconstriction also differ between clobetasol propionate and norepinephrine.

[0276] A modified MIRVASO 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 the increased dose on skin whitening in a vehicle similar to that used for MIRVASO.

[0277] The corresponding skin whitening results for the two formulations are shown in Figure 10. Norepinephrine solution and commercially available MIRVASO® gel (0.5% brimonidine tartrate) are also included for comparison.

[0278] Modified MIRVASO gel (1.5% brimonidine tartrate 19-0155-0098 / F1) caused a substantial increase in the intensity and duration of skin whitening compared to commercially available MIRVASO® gel (0.5% brimonidine tartrate).

[0279] On the other hand, the intensity of skin whitening did not last for a sufficiently long period of time to solve the technical problems in this invention.

[0280] This performance limitation is also related to the unsuitability of the MIRVASO vehicle for radiation dermatitis. As mentioned above, the presence of titanium dioxide particles in the MIRVASO vehicle likely inhibits and interferes with the radiation dose associated with the high-energy electromagnetic waves used.

Claims

1. A composition, suitable for topical administration, which is aqueous and contains a vasoconstrictor, wherein the composition is in the form of an emulsion containing a liquid crystal, the vasoconstrictor is selected from brimonidine or a salt thereof, and the vasoconstrictor is Polyethylene glycol combined with propylene glycol, Alone or in combination, a hydrophilic film-forming agent selected from polyvinylpyrrolidone / vinyl acetate copolymer and polyvinylpyrrolidone, Glycerin and, An emulsifier selected from a combination of PEG-75 stearate and glyceryl monostearate, and a combination of polyoxyethylene-20 sorbitan monostearate (POLYSORBATE-60) and cetostearyl alcohol, Oleic acid or oleyl alcohol, An oil phase suitable for obtaining an emulsion containing liquid crystals and A composition characterized by being in a solvent system phase containing [a specific substance].

2. The composition according to claim 1, characterized by containing oleic alcohol.

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

4. The composition according to any one of claims 1 to 3, characterized in that the oil phase comprises, alone or in combination, cetyl alcohol and stearyl alcohol, and / or, alone or in combination, triglyceride esters of coconut / palm kernel-saturated caprylic and caprin fatty acids and plant-derived glycerol, and stearyl ether of polypropylene glycol (PPG)-11.

5. The composition according to claim 4, characterized by comprising a combination of cetyl alcohol and stearyl alcohol.

6. The composition according to claim 4 or 5, characterized in that it is a combination of caprylic and caprin fatty acids saturated with coconut / palm kernels, triglyceride esters of plant-derived glycerol, and the stearyl ether of PPG-11.

7. A composition according to any one of claims 1 to 6, characterized by containing xanthan gum.

8. The composition according to claim 7, characterized in that it contains xanthan gum at a concentration between 0.1% by weight and 1.5% by weight of the total weight of the composition.

9. The composition according to claim 7, characterized in that it contains xanthan gum at a concentration between 0.2% by weight and 1% by weight of the total weight of the composition.

10. The composition according to claim 7, characterized in that it contains xanthan gum at a concentration between 0.2% by weight and 0.5% by weight of the total weight of the composition.

11. A composition according to any one of claims 1 to 10, characterized by comprising a natural or synthetic antioxidant or a free radical scavenger.

12. The composition according to claim 11, characterized in that the antioxidant is selected, either alone or in a mixture, from butylated hydroxyanisole (BHA), DL-tocopherol, butylated hydroxytoluene (BHT), propionaldehyde, ascorbate, palmitate, or glutathione.

13. The composition according to claim 11, characterized in that the antioxidant is selected from BHA and / or DL-tocopherol.

14. The composition according to any one of claims 1 to 13, characterized in that it contains brimonidine or a salt thereof in a concentration between 0.15% by weight and 3.00% by weight of the total weight of the composition.

15. The composition according to any one of claims 1 to 13, characterized in that it contains brimonidine or a salt thereof at a concentration between 0.50% by mass and 2.50% by mass of the total weight of the composition.

16. The composition according to any one of claims 1 to 13, characterized in that it contains brimonidine or a salt thereof at a concentration between 0.75% by mass and 1.50% by mass of the total weight of the composition.

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

18. The composition according to any one of claims 1 to 17, characterized in that the brimonidine salt is brimonidine tartrate.

19. The composition according to any one of claims 1 to 18, characterized by comprising, alone or in combination, a paraben selected from methylparaben, propylparaben, or isopropylparaben, phenoxyethanol, sodium benzoate, phenylethyl alcohol, and / or EDTA.

20. A composition according to any one of claims 1 to 19 for use as a pharmaceutical.

21. A composition for use according to claim 20, for the prevention and / or treatment of dermatitis caused by radiation.

22. The composition for use according to claim 20, for the prevention and / or treatment of dermatitis caused by radiation during radiotherapy.

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