EP4294364A2 - Emulsionszusammensetzung und verwendungen davon bei der vorbeugung und/oder behandlung von durch strahlung verursachten hautschäden - Google Patents

Emulsionszusammensetzung und verwendungen davon bei der vorbeugung und/oder behandlung von durch strahlung verursachten hautschäden

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Publication number
EP4294364A2
EP4294364A2 EP22706816.0A EP22706816A EP4294364A2 EP 4294364 A2 EP4294364 A2 EP 4294364A2 EP 22706816 A EP22706816 A EP 22706816A EP 4294364 A2 EP4294364 A2 EP 4294364A2
Authority
EP
European Patent Office
Prior art keywords
composition according
combination
composition
brimonidine
skin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22706816.0A
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English (en)
French (fr)
Inventor
Gareth Winckle
Philippe Andres
Janusz Czernielewski
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tarian Pharma SAS
Original Assignee
Tarian Pharma SAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tarian Pharma SAS filed Critical Tarian Pharma SAS
Publication of EP4294364A2 publication Critical patent/EP4294364A2/de
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1274—Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • UV ultraviolet
  • UVA ultraviolet
  • UVB ultraviolet
  • IR infrared radiation
  • ionizing radiation such as X-rays and alpha
  • befa ionizing radiation
  • gamma radiation even radiation composed of protons.
  • MIRVASO® gel (0.5% w/w brimonidine ⁇ ar ⁇ ra ⁇ e) is ⁇ indicated for the symptomatic treatment of facial erythema associated with rosacea in adults.
  • Brimonidine is best known as a highly selective alpha2-adrenergic receptor agonist. Brimonidine is ⁇ 1000 times more selective for alpha2-adrenergic receptors than for alpha 1-adrenergic receptors.
  • compositions intended for topical application may cause side effects which may limit their use and therefore their effectiveness.
  • certain active agents have the major disadvantage of inducing irritation which can lead to poor tolerance of the product. This can thus create in the patient a behavior of non-compliance with the treatment and dissatisfaction with the said treatment.
  • emollients applied a few hours after the radiation session (for example DEXERYL®, TOPICREME®) moisturize the skin and bring transitory well-being to the patient.
  • radiodermatitis lesions such as creams based on hyaluronic acid, TETA® cream or BIAFINE®. It is nevertheless recalled here that these treatments have not been proven to be effective and that, on the contrary, clinical studies have concluded that there is no effect.
  • hydrophilic compounds distribute more freely in viable tissues and are cleared by circulation from the underlying local vasculature.
  • an optimal and complex compositional balance must be identified to modulate variables such as thermodynamics, residual surface solubility, solubility in the stratum corneum and penetration and persistence in viable tissues (solvent pull/drag effects).
  • the optimized topical composition thus proposed by the Applicant improves the duration of vasoconstriction (with a duration of at least 14 up to 24 hours) as well as the power thereof without disturbing the passage of radiation through the skin, which would compromise its effectiveness.
  • an emulsifier chosen from the association PEG-75 sfearafe and glyceryl monosfearafe and the association polyoxyefhylene-20 sorbifan monosfearafe (polysorbafe-60) and cefosfearyl alcohol;
  • an oily phase suitable for obtaining an emulsion preferably water in oil or oil in water, more preferably oil in water, comprising liquid crystals.
  • Figure 1 shows the stability measurements using the LUMiSize® for the compositions 19-0155.0045 (W/O emulsion based on Brij/Arlamol), 19-0155.0065P (W/O emulsion based on Brij/Arlamol), 19 -0155.0090 (W/O emulsion based on Gelof 64) and 19-0155.0091 (W/O emulsion based on Polawax).
  • Figure 3 represents the viscosity measurements obtained with different compositions using the reference composition 19-0155-0090P/F3 according to the process conditions carried out within the framework of example 5 and more particularly of Table 14.
  • the topical composition according to the invention is characterized in that it is in the form of an emulsion, preferably water in oil or oil in water, more preferably oil in water, comprising liquid crystals.
  • Liquid crystals are ⁇ infinite aggregates of molecules that greatly improve solubilization and ⁇ facilitate emulsification.
  • Liquid crystal formulations offer several advantages as vehicles for topical compositions, including:
  • the topical composition according to the invention is characterized in that it comprises a vasoconstrictor chosen from brimonidine or its salts, in a solvent phase comprising:
  • hydrophilic film-forming agent chosen from a Polyvinylpyrrolidone/Vinyl Acetate copolymer (KOLLIDON VA 64®), polyvinylpyrrolidone (PVP) in a non-crosslinked, crosslinked or acetate form, taken alone or in combination, preferably a Polyvinylpyrrolidone/Vinyl Acetate copolymer as agent hydrophilic film former; - glycerin;
  • an oleic acid or an oleic alcohol preferably an oleic alcohol
  • an oily phase suitable for obtaining an emulsion preferably water in oil or oil in water, more preferably oil in water, comprising liquid crystals.
  • salts or pharmaceutically acceptable salt(s) are meant those salts of a compound of interest which are safe and effective for topical use in mammals and which possess a desired biological activity.
  • Pharmaceutically acceptable salts include salts of acidic or basic groups present in the specified compounds.
  • Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate salts.
  • Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.
  • the brimonidine used in the compositions according to the invention is brimonidine tartrate, although the salt form presents a challenge from a stability point of view for an emulsion, water-in-oil or oil-in-water formulation.
  • the salts can interact with surfactants and nonionic polymers and reduce their aqueous solubility and thus harm the physical stability of the semi-solid formulation.
  • the salt form of the active generates a relatively high aqueous solubility and advantageously allows the design and evaluation of aqueous-based formulations, which can offer improved performance in terms of sensory and local tolerance.
  • Concentrations of between 0.15% and 3.00% of brimonidine or its salts, preferably brimonidine tartrate, by weight of the total weight of the composition are preferably used to obtain the effectiveness and an improved duration of the effect until 24 hours after application while preventing any risk of systemic exposure.
  • the composition according to the invention comprises brimonidine or its salts, preferably brimonidine tartrate at a concentration of between 0.50% and 2.50% by weight of the total weight of the composition, preferably between 0.75 % and 1.50% w/w, plus preferably between 1.00% and 1.50% w/w, even more preferably 1.00% or 1.50% W/W
  • the concentration of brimonidine, preferably of brimonidine tartrate, and the dose thus applied is advantageously adapted according to the site of application.
  • the oily phase of the water-in-oil or oil-in-water emulsion composition comprising liquid crystals according to the invention comprises cetyl alcohol and stearyl alcohol, taken alone or in combination, and/or a triglyceride ester of saturated caprylic and capric fatty acids from coconut/palm kernel and vegetable glycerol (Miglyol 812N), a Polypropylene Glycol (PPG)-l l stearyl ether (Arlamol PSI 1 E-LQ-[RB]) , taken alone or in combination.
  • a triglyceride ester of saturated caprylic and capric fatty acids from coconut/palm kernel and vegetable glycerol (Miglyol 812N)
  • PPG Polypropylene Glycol
  • Arlamol PSI 1 E-LQ-[RB] taken alone or in combination.
  • the oily phase comprises a combination of cetyl alcohol and stearyl alcohol.
  • the oily phase of the water-in-oil or oil-in-water emulsion composition comprising liquid crystals according to the invention preferably comprises cetyl alcohol, stearyl alcohol and oleyl alcohol, taken in combination, at a concentration of between 1% and 15% by weight of the total weight of the composition, preferably between 2.5% and 10% w/w.
  • the oily phase comprises a combination of triglyceride ester of saturated coconut/palm kernel caprylic and capric fatty acids and glycerol of plant origin and PPG-11 stearyl ether.
  • the oily phase of the water-in-oil or oil-in-water emulsion composition comprising liquid crystals according to the invention preferably comprises the triglyceride ester of caprylic and capric fatty acids saturated with coconut/palm kernel and glycerol of plant and PPG-11 stearyl ether taken in combination at a concentration of between 5% and 10% by weight of the total weight of the composition.
  • the topical composition according to the invention is characterized in that it comprises polyethylene glycol (PEG) in combination with propylene glycol (PG).
  • PEG polyethylene glycol
  • PG propylene glycol
  • PEGs polyethylene glycols
  • the high solubilizing capacity of PEGs can ⁇ result in suboptimal thermodynamics for topical administration, and ⁇ when used at high concentrations, product transformation, often associated with evaporation of volatile components such as water, cannot ⁇ be used to enhance dermal release.
  • these features may reduce delivery efficiency, although high concentrations are possible; much of the applied dose of topical agents remains on the surface of the skin or is lost to the environment by contact transfer.
  • the PEGs are essential to the topical formulation.
  • PEG-400 or PEG-400 SR has relatively low penetration into the stratum corneum due to its molecular weight and high polarity (low partition coefficient), it is the preferred PEG used in the composition.
  • emulsion, water in oil or oil in water according to the invention to reduce the rate of precipitation of the active agent at the surface of the skin e ⁇ in the upper layers of the stratum corneum, for surface solubilization. This promotes sustained delivery of brimonidine fartrafe into the viable layers of the skin and ⁇ specifically into the vasculature of the dermal plexus where the target site of brimonidine fartrafe is located.
  • PEG-400 or PEG-400 SR has adequate solubility to promote better retention of brimonidine fartrafe in solution on the surface of the skin and in the upper layers of the stratum corneum.
  • PG As an antibacterial agent, PG has an effect similar to that of ethanol; however, it is ⁇ slightly less effective against mold with a profile comparable to glycerin.
  • PG also exhibits some volatility: although a fraction of the applied dose evaporates upon application to the skin or at least within 37 hours after application, a much larger portion penetrates the stratum corneum. e ⁇ penetrates the deeper layers of the skin.
  • the relatively rapid penetration of PG through the stratum corneum and its volatility can deplete the residual vehicle of its solvent, increase the thermodynamic activity of the active in the vehicle and thus modify the driving force of diffusion.
  • penetration and permeation of PG can also disrupt the stratum corneum lipid barrier and therefore reduce diffusional resistance.
  • PG thus has favorable physico-chemical properties in terms of penetration e ⁇ skin permeation e ⁇ es ⁇ absorbed through the skin. Therefore, solutes that are ⁇ easily dissolved by PG (i.e. high solvent/vehicle affinity) may advantageously benefit from enhanced skin penetration via a solvent resistance mechanism or pulling effects.
  • a fortiori, PG is ⁇ known to penetrate the skin faster than most active ingredients and therefore the precipitation of the active ingredient on the surface of the skin will limit its duration of action.
  • concentrations of PG are generally limited to about 20% w/w or less, to avoid local irritant reactions and cause systemic toxicity issues.
  • the composition according to the invention comprises polyethylene glycol (PEG) at a concentration of 10% by weight of the total weight of the composition in combination with propylene glycol (PG) at a concentration of 20% by weight of the total weight of composition.
  • PEG polyethylene glycol
  • PG propylene glycol
  • the composition according to the invention comprises the hydrophilic film-forming agent, taken alone or in combination, at a concentration of between 0.1% and 1.5% by weight of the total weight of the composition, preferably between 0. 25% and 1.4%, more preferably between 0.5% and 1.3%, even more preferably between 0.75 and 1.25, even more preferably 1%.
  • Glycerin (glycerol) is a well-known humectant that can increase water retention in the stratum corneum and improve hydration.
  • the composition according to the invention comprises glycerin at a concentration of between 1% and 20% by weight of the total weight of the composition, preferably between 2% and 15%, more preferably between 3% and 10 %, even more preferably 4%.
  • composition according to the invention, it comprises the combination PEG-75 stearate and glyceryl monostearate (Gelo ⁇ 64) which contains fatty ingredients having a melting point of between 46 and 66°C.
  • the most important step after emulsification which is carried out at a temperature of around 65 ⁇ 5°C, is the cooling step.
  • the decrease in temperature causes fatty ingredients to crystallize when they reach their transition temperature.
  • the fatty emulsifiers/co-emulsifiers organize themselves around the oil droplets.
  • the lipophilic co-emulsifier ⁇ remains mainly in the oil droplets while the hydrophilic emulsifian ⁇ and the amphiphilic fatty aliphatic alcohol ⁇ remain at the interface between the oil droplets and the continuous aqueous phase of the emulsion .
  • the composition according to the invention comprises oleic acid or oleic alcohol at a concentration of between 0.1% and 7% by weight of the total weight of the composition, preferably between 1% and 5%, more preferably 2.5%.
  • the topical composition according to the invention also comprises xanthan gum as gelling agent.
  • the composition according to the invention comprises xanthan gum at a concentration of between 0.1% and 1.5% by weight of the total weight of the composition, preferably between 0.2% and 1%, more preferably respectively of 0.2-0.5% for xanthan gum.
  • a flexible mixed film is thus advantageously formed on the surface of the skin with xanthan gum and the Polyvinylpyrrolidone/Vinyl Acetate copolymer (KOLLIDON VA 64®) in addition to the other non-volatile solvents, PG and PEG, making it possible to create a reservoir of brimonidine , preferably brimonidine tartrate, and thus slow down the precipitation of brimonidine and prolong its duration of action.
  • brimonidine preferably brimonidine tartrate
  • the topical composition according to the invention also comprises a natural or synthetic antioxidant, or a free radical scavenger.
  • the antioxidant is preferably chosen from butylated hydroxyanisole (BHA), DL-tocopherol, butylhydroxytoluene (BHT), propaldehyde, ascorbate palmitate or glutathione, taken alone or as a mixture, advantageously as a mixture, preferably BHA and/or DL-tocopherol.
  • the antioxidant is preferably used in the emulsion, water-in-oil or oil-in-water compositions according to the invention at a concentration of between 0.01% and 4.0% by weight of the total weight of the composition, more preferably between 0 1.1% and 1.0%, even more preferably 0.1%, for example BHA at 0.1% w/w and/or DL-tocopherol at 0.1% w/w.
  • the topical composition according to the invention also comprises a paraben chosen from methyl paraben, propyl paraben or isopropyl paraben, taken alone or in combination.
  • a paraben chosen from methyl paraben, propyl paraben or isopropyl paraben, taken alone or in combination.
  • the composition according to the invention comprises the paraben taken alone or in combination at a concentration of between 0.01% and 0.5% by weight of the total weight of the composition, preferably between 0.1% and 0, 4%, more preferably 0.3%.
  • the composition according to the invention further comprises phenoxyethanol, preferably at a concentration of between 0.15% and 1.5%, more preferably between 0.4% and 1.25%, even more preferably between 0. 5% and 1.1%, more preferably still 1% w/w; sodium benzoate, preferably at a concentration of between 0.05% and 0.5%, more preferably between 0.1% and 0.3%, even more preferably 0.2% w/w; phenylethyl alcohol as an alternative preservative, preferably at a concentration of between 0.1% and 1%, more preferably between 0.25% and 0.75%, even more preferably 0.5% w/w; and/or EDTA as chelating agent aiding in the preservation and stability of the composition, preferably at a concentration of 0.2% W/W ⁇
  • the composition comprises phenoxyethanol, sodium benzoate, phenylethyl alcohol and EDTA taken in combination.
  • a hydrophilic solvent phase with solvents that have hygroscopic, humectant and skin conditioning properties, including PG and glycerin, improves the solubility of brimonidine tartrate in the stratum corneum and increase the water content.
  • antioxidants improves the stability of the active ingredient e ⁇ of the oily phase.
  • oily phases used have been selected to promote the formation of the emulsion, physical stability, e ⁇ obtaining the desired microstructure e ⁇ to help the cutaneous delivery of the active while presenting performances appropriate sensory.
  • the water-in-oil or oil-in-water emulsion compositions according to the invention thus make it possible to improve and ⁇ to prolong the cutaneous administration of brimonidine ⁇ ar ⁇ ra ⁇ e ⁇ to meet the needs of patients with adequate local vasoconstriction e ⁇ prolonged e ⁇ protection of the epidermis e ⁇ of the upper dermis against reactive oxygen species e ⁇ inflammatory mediators.
  • compositions according to the invention are easy to apply and can be applied to potentially irritated skin.
  • the topical compositions according to the invention have a pH between 3.5.0 and 6.5, preferably between 4.0 and 5.5, more preferably 4.5.
  • the water-in-oil or oil-in-water emulsion compositions according to the invention have been designed to contain relatively high amounts of glycols, for example 20% PG and 10% PEG-400. Such relatively high concentrations of these components do not necessarily support stability and maintenance of the microstructure because they can disturb the interface and solubilize the emulsifiers and co-emulsifiers. Moreover, the addition of a relatively high concentration of an active salt, brimonidine tartrate presents a possibility of physical destabilization of the e ⁇ interface of the emulsion.
  • Another object of the invention relates to an emulsion composition, water in oil or oil in water, preferably oil in water, according to the invention for its use as a medicament.
  • the water-in-oil or oil-in-water emulsion composition according to the invention is used for the prevention and/or treatment of damage caused by radiation, whether this radiation is photons or protons and they are natural, therapeutic or accidental, including ultraviolet (UV) including UVA e ⁇ UVB which can cause sunburn, rays in the visible range, infrared radiation (IR), or even ionizing radiation such as X-rays and alpha, beta, gamma radiation or even proton beams.
  • UV ultraviolet
  • UVA e ⁇ UVB ultraviolet A e ⁇ UVB which can cause sunburn, rays in the visible range, infrared radiation (IR), or even ionizing radiation such as X-rays and alpha, beta, gamma radiation or even proton beams.
  • the water-in-oil or oil-in-water emulsion composition according to the invention is used for the prevention and/or treatment of dermatitis resulting from treatment by radiotherapy, for example by X-rays.
  • DMSO appears to be an excellent solvent for brimonidine fartrafe and saturation was not reached even after the addition of 8.5% w/w of brimonidine fartrafe.
  • brimonidine tartrate concentrations of 1% or 1.5% of brimonidine tartrate are ⁇ used, it is ⁇ possible that the active ingredient is ⁇ at around 30% or 50% saturation, respectively, in the aqueous solvent phase of the primary formulation before application. However, when applying the formulation to the surface of the skin, the water will evaporate relatively quickly.
  • the average values are between 99.36% and 101.45% with a relative standard deviation of less than 1%.
  • Solvent blends without Glucam E20 show the most favorable stability profile and glycerin appears to improve stability.
  • Glucam E10 was included in the compositions at a concentration of 5%, the stability of brimonidine fartrafe improved. Bimonidine tartrate assay values tend to decrease with increasing Glucam concentration.
  • the most stable mixture of solvents was obtained for M8 (30% Transcutol in water) then for Ml (DMSO 10%, Glucam E105% and Glycerin 5% in water).
  • LUMiSizer® Centrifugation and a more quantitative rapid screening tool, LUMiSizer® has been used to maximize efficiency and to facilitate screening of different compositions.
  • compositions mentioned in Tables 5-8 below were evaluated using a standardized LUMiSize® protocol: duration of 3 hours; temperature of 40°C and centrifugation at 4000 ⁇ ours/min.
  • Table 5 19-0155.0045 (oil-in-water emulsion; BRU/ARLAMOL base; active)
  • Table 6 19-0155.0065P (oil-in-water emulsion; Brij / Arlamol base; vehicle)
  • compositions comprising the active substance based on Gelof 64 (19-0155.0090) and based on Polawax (19-0155.0091) on the other hand and surprisingly have a physical stability similar to that of the vehicle 19-0155.0065P.
  • compositions based on BRIJ/ARLAMOL are beneficial observations.
  • composition 19-0155.0076/F2 being a little more stable than composition 19-0155.0076/F2 (showing exudation ⁇ after storage for 3 months at 40°C and ⁇ a slightly higher instability index).
  • Table 12 Compositions tested for the evaluation of the stabilization of polymers at
  • Example 5 Evaluation of the impact of the variation of different stages of the manufacturing process of an oil-in-water emulsion composition
  • Table 14 Summary of Process Variables Assessed Using Base Composition 19-0155-0090P
  • Step 2 Weighing and adding the KOLLIDON to the mixture obtained in step 1. Mixing with the deflocculating or dispersing blade until homogenization.
  • Step 5 no more than 20 minutes before emulsification, the phenoxyethanol is introduced into the mixture obtained in step 4.
  • Step 6 weighing and adding all the excipients constituting the fatty phase. Heat up to 70°C and mix until homogenized.
  • Stage 7 at 70°C, pour the mixture of phase B obtained in stage 6 into the mixture of phase A obtained in stage 5, mixing for 10 minutes at 500 ⁇ ours/min.
  • Step 8 Remove the mixture obtained in step 7 from the heating plate, allow to cool to 35°C while stirring at 200-300 ⁇ ours/min.
  • Step 9 Between 30°C and 35°C, the formulation increases in viscosity and a spatula is used to remove the product from the sides of the beaker.
  • Step 10 Once the mixture obtained in step 9 is homogeneous, adjust to approximately pH 4.5 - 5 using a 10% citric acid solution.
  • Step 1 1 Once the pH has been adjusted, mix using the deflocculating / dispersing blade for 20 minutes at approximately 200 ⁇ ours/min.
  • Step 12 once step 1 1 is completed, complete with water (qsp).
  • Step 1 weighing e ⁇ addition of water e ⁇ of methyl paraben in the beaker.
  • Step 2 Weighing and adding the KOLLIDON to the mixture obtained in step 1. Mixing with the paddle stirrer until homogenization.
  • Step 3 Addition of xanthan gum previously dispersed in glycerine to the mixture obtained in step 2 at 65°C.
  • Step 4 weighing and adding all the excipients constituting the fatty phase. Heat up to 70°C and mix until homogenized.
  • Step 7 While cooling, introduce PG e ⁇ PEG-400 into the mixture obtained in step 6.
  • Step 8 at 35°C - 40°C, weigh and add phenoxyethanol to the mixture obtained in step 7.
  • Step 10 Once the mixture obtained in step 9 is homogeneous, adjust to approximately pH 4.5 - 5 using a 10% citric acid solution.
  • Step 1 1 Once the pH has been adjusted, mix using the paddle stirrer for 30 minutes at approximately 200 ovens/min.
  • Step 12 once step 1 1 is completed, complete with water (qsp).
  • Such a microstructure maximizes the specific surface of the liquid crystal/lamellar gel phases to facilitate the transfer of the active ingredient into the skin and thus improve vasoconstriction, in terms of intensity of vasoconstriction and prolonged duration of vasoconstriction.
  • the size of the droplets is therefore influenced by the process used and the “Croda” process tends to reduce the size of the droplets to a greater extent than the “Defloculator” process. This is most likely due to the use of a high shear mixer during the emulsification process and the subsequent use of a paddle stirrer.
  • the active phase (including the active) is ⁇ introduced after emulsification, it must not be heated.
  • Microsfrucfure does not appear to be significantly affected by this minor formulation change when manufactured using the “deflocculator” process.
  • Example 6 Evaluation of the Effect on Skin Whitening of Different Compositions Using an In Vivo Vasoconstriction Model
  • compositions were tested in triplicate using the in vivo vasoconstriction protocol as described below. 60 microliters of each composition were applied once in a blind random manner at 8 a.m. to the upper chest, using a positive displacement pipette, on a 10 cm2 area defined using plastic O-rings.
  • composition 19-0155,0086A/F 1 produced a slightly better overall profile than the Gelo ⁇ 64 based compositions ( 19-0155-0083/F 1 and ⁇ 19-0155-0087/F 1). It should be noted that composition 19-0155.0086A/F 1 also contains oleic alcohol (KOLLICREAM OA, 2.5%) and KOLLIDON VA-64, which improve and prolong twice the cutaneous administration of the locally applied asset.
  • KOLLICREAM OA oleic alcohol
  • KOLLIDON VA-64 which improve and prolong twice the cutaneous administration of the locally applied asset.
  • composition based on Gelo ⁇ 64 does not impart any polymer or oleyl alcohol while the composition based on Gelo ⁇ 64 19-0155-0087/Fl imparts KOLLIDON VA-64 e ⁇ oleic alcohol. Both Gelo ⁇ 64-based formulations demonstrated superior physical stability compared to the Polawax-based formulation.
  • Such oil-in-water emulsions have therefore demonstrated improved performance characteristics in terms of onset, intensity and duration of skin whitening.
  • Example 7 Evaluation of the Effect on Skin Whitening of Different Compositions Using an In Vivo Vasoconstriction Model
  • compositions and physical stability data for Gelo ⁇ 64 based emulsions and Polawax based emulsions tested are described in Tables 17 and 18 below.
  • Table 17 Detailed compositions of Gelo ⁇ 64 emulsions tested using the in vivo vasoconstriction model
  • Table 18 Detailed compositions of Polawax NF emulsions tested using the in vivo vasoconstriction model
  • the Gelot-based compositions thus used are optimized versions of the Gelot 64 emulsion (19-0155-0090/Fl and 19.0155-0103/Fl) while the Polawax emulsions are optimized variants of the Polawax emulsion (19- 0155.0091 /Fl).
  • compositions were tested in triplicate using the in vivo vasoconstriction protocol as described above.
  • Gelo ⁇ 64 (19-0155-0102/F5) and Polawax (19-0155-0132/F2) emulsion formulations generated similar vasoconstriction profiles.
  • the degree of vasoconstriction is ⁇ similar, approximately 1-1.5 after application e ⁇ to the maximum value after approximately 4 hours.
  • Vasoconstriction intensity remained in the 3.0 range up to 14 hours after application and decreased to 1.0-1.5 after 24 hours.
  • Figure 7 presents the average skin whitening profiles ⁇ standard deviation of the active formula 19-0155-0102/F5 e ⁇ of the corresponding vehicle 19-0155-0102P/F2 e ⁇ also demonstrates the excellent reproducibility of the vasoconstriction test ⁇ .
  • Example 9 Evaluation of the efficacy on a model of UV-induced erythema
  • Active compositions comprising brimonidine ⁇ ar ⁇ ra ⁇ e and ⁇ vehicles listed in Table 19 were evaluated using the UV-induced erythema model.
  • compositions were applied using the protocol as specified below. This involves application in the evening before UV irradiation and ⁇ 2 hours before UV irradiation in three healthy volunteers.
  • Active compositions containing 1.5% brimonidine ⁇ ar ⁇ ra ⁇ e demonstrated substantial reductions in erythema scores compared to vehicles. Additional benefits in terms of anti-erythematous effects were ⁇ observed when 1.5% w/w of brimonidine ⁇ ar ⁇ ra ⁇ e is ⁇ associated with antioxidants.
  • BHA and ⁇ -tocopherol have been used as model antioxidants at concentrations of 0.1% and 1% w/w.
  • Formulations containing 1% BHA or 1% ⁇ -tocopherol demonstrated the most potent anfi-eryphemia effects and effectively inhibited 2 MED.
  • Formula 19-0155.0102/F5 (Gelo ⁇ 64 O/W liquid crystal emulsion) produced the greatest anti-erythema effect.
  • the skin whitening model allows to differentiate the skin whitening capacity caused by several actives applied in different formulations in terms of onset, intensity and duration of skin whitening.
  • Norepinephrine (noradrenaline) solution produced rapid and intermediate skin whitening 1 hour after application: however, the effect began to wear off after the 4 hour observation interval. Whitening was at 0.5 or less after 10 hours and returned to baseline only after 16 hours. While the initial effects were promising, the duration and intensity of the effect was not sufficient.
  • clobetasol propionate cream exhibited a len ⁇ onset of action with a gradual increase over 2 hours to a peak whitening score of 2.0 between 14 at 4 p.m. There is a rapid reduction in whitening starting at 4 p.m. and returning to baseline at 12 a.m.
  • the slower onset of action ⁇ of clobetasol bleaching can ⁇ be linked to the physico-chemical characteristics of the active ingredient, whereby its lipophilic character results in the formation of a reservoir and a more limited distribution in the viable epidermis by compared to the more hydrophilic norepinephrine. It is also important to note that the pharmacodynamic mechanisms of vasoconstriction are also different for clobetasol propionate and norepinephrine.
  • a modified formula of the MIRVASO type was prepared with a high dose of 1.5% w/w of brimonidine tartrate (19-0155-0098/Fl). This ⁇ e evaluation was conducted to assess the impact of an increased dose on skin whitening in a vehicle similar to MIRVASO.
  • the modified MIRVASO gel (1.5% Brimonidine tartrate 19-0155-0098/Fl) caused a substantial increase in the intensity e ⁇ of the duration of skin whitening compared to the marketed MIRVASO® gel (0.5 % Brimonidine tartrate).
  • the intensity of the whitening of the skin did not persist for a prolonged period of time as desired to solve the technical problem according to the invention.

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EP22706816.0A 2021-02-19 2022-02-18 Emulsionszusammensetzung und verwendungen davon bei der vorbeugung und/oder behandlung von durch strahlung verursachten hautschäden Pending EP4294364A2 (de)

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