Classifications

• • 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
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
• • 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

Definitions

• the present invention relates to an external preparation for treating skin diseases.
• Rosacea is a chronic inflammatory skin disease with symptoms such as erythema, papules, pustules, telangiectasia, paroxysmal flushes, and rhinophyma.
• Rosacea patients experience skin discomfort such as hot flashes and burning sensations due to the above rosacea symptoms.
• rosacea symptoms usually appear on the face and can be recognized visually, rosacea patients tend to suffer from low self-esteem and social life disorders, and may even lead to depression and social anxiety disorder.
• rosacea The cause of rosacea is unknown, but it is believed that changes and abnormalities in the innate immune response are involved. Sun exposure, psychological stress, low temperature, high temperature, exercise, spices, alcohol and the like are known to exacerbate rosacea.
• symptomatic treatment is the main treatment for rosacea.
• Specific treatment methods include a treatment method using an external agent, a treatment method using an internal medicine, and a treatment method using a surgical means.
• metronidazole ivermectin, azelaic acid, brimonidine, oxymetazoline, sulfur sulfacetamide, etc. are used.
• vitamin A derivatives such as isotretinoin; tetracycline antibiotics such as minocycline and doxycycline; macrolide antibiotics such as erythromycin and azithromycin, etc. are used.
• laser treatment and the like are used in treatments that use surgical means.
• Patent Document 1 discloses (a) timolol or a pharmaceutically acceptable salt thereof, and (b) ivermectin, metronidazole, praziquantel and pharmaceutically acceptable salts thereof.
• the invention is described as a combination for topical use comprising an active compound useful for the treatment of rosacea selected from: Patent Document 1 describes that the combination of component (a) with component (b) used as an external preparation resulted in a more significant anti-edema effect than when component (b) was administered alone. ing.
• Patent Document 1 describes solutions, lotions, emulsions with liquid viscosity, emulsions with semi-liquid viscosity, emulsions with semi-solid viscosity, emulsions with solid viscosity, creams, gels, and ointments as dosage forms for topical administration.
• Patent Document 1 The combination described in Patent Document 1 can be suitably used for treating skin lesions of rosacea patients. However, there are cases where a sufficient therapeutic effect cannot be obtained depending on the condition of the rosacea patient. Under such circumstances, further development of external preparations is underway.
• the present invention provides, for example, the following external preparations.
• an external preparation having a high therapeutic effect is provided for severe rosacea patients.
• the external preparation according to the present invention is used to treat at least one skin lesion selected from the group consisting of papules, pustules, and erythema, preferably papules, pustules, and erythema.
• the topical agent contains metronidazole.
• the external preparation is applied to severe rosacea patients.
• the external preparation is applied to the affected area twice a day.
• "severe” means an IGA score of 4, for example.
• “Treatment” also includes preventing, treating, or preventing recurrence of at least one skin lesion selected from the group consisting of papules, pustules, and erythema.
• IGA Investigator Global Assessment
• the external preparation is preferably IGA (Investigator Global Assessment), which is a comprehensive severity assessment (see, for example, Guy Webster et al., Journal of Dermatological Treatment, 2017, vol.28, No.5, 469-474) is applied to rosacea patients with an IGA score of 4.
• the "IGA score" is determined according to the following criteria.
• Successful treatment of rosacea is usually defined as an IGA score of 0 or 1.
• inflammatory rash includes papules and pustules.
• a "papule” is a localized raised skin lesion that is palpable.
• a “pustule” is an elevated skin lesion with a capsule on the canopy and a blister containing pus (mainly neutrophils) inside. The pustules are usually white to yellow in color.
• erythema is a reddish macular caused by vasodilation and hyperemia in the papillae and subpapillae of the dermis, without elevations and depressions on the skin surface.
• “many small to large papules/pustules” means that the total number of small papules/small pustules and large papules/large pustules is 21 or more in the entire face.
• the term “whole face” means the area from the tip of the chin to the hairline and from the left ear to the right ear.
• “Diameter” means the maximum distance between two points on the circumference of papules, pustules, and the like.
• the external preparation according to the present invention has a particularly high therapeutic effect when applied to severe rosacea patients.
• Rosacea is caused by an increase in reactive oxygen species (H 2 O 2 , OH radicals, O 2 - , etc.) associated with skin inflammation, an abnormal immune response, microorganisms living in the skin epidermis and hair follicles, and Demodex mites. (Demodex folliculorum). These causes may be particularly prominent in cases of severe rosacea.
• reactive oxygen species H 2 O 2 , OH radicals, O 2 - , etc.
• the topical agent according to the present invention has multiple effects such as the reduction of reactive oxygen species from human neutrophils possessed by metronidazole, the suppression of immune response by suppressing the production of TNF- ⁇ , and the killing of microorganisms and Demodex mites. It can be expressed effectively. This is believed to have a high therapeutic effect, especially in severe rosacea patients.
• treatment means that at least one effect of reducing the size of papules and/or pustules, reducing the number of papules and/or pustules, and alleviating symptoms of erythema is obtained. do. This results in a lower IGA score, preferably an IGA score of 4 to 0 or 1.
• metronidazole The external preparation according to the present invention contains metronidazole.
• the chemical name for metronidazole is 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanol and has the following structural formula.
• Examples of methods for producing metronidazole include the following methods. That is, N,N'-ethylenebisacetamide obtained by reacting ethylenediamine and acetic acid is sequentially treated with calcium oxide and Raney nickel to prepare 2-methylimidazole, and then mixed acid (nitric acid and sulfuric acid) is used to prepare nitro to prepare 2-methyl-4-nitroimidazole. Metronidazole can be produced by reacting 2-methyl-4-nitroimidazole thus prepared with ethylene oxide or 2-chloroethanol.
• the content of metronidazole is preferably 0.5 to 1.5% by mass, more preferably 0.6 to 1.2% by mass, more preferably 0.7 to 0.7% by mass, based on the total mass of the external preparation. It is more preferably 0.9% by mass, and particularly preferably 0.7 to 0.8% by mass.
• microorganisms and mites (Demodex folliculorum) inhabiting the skin epidermis and hair follicles can be preferably killed.
• the external preparation (pharmaceutical composition) according to the present invention may contain additives.
• Additives include, but are not limited to, bases, wetting agents, thickeners, emulsifiers, emulsifying aids, preservatives, stabilizers, pH adjusters and the like.
• bases examples include hydrophobic bases, hydrophilic bases and water.
• base means an additive having a content of 40% by mass or more (preferably 50 to 99% by mass) relative to the total mass of the external preparation.
• the hydrophobic base is not particularly limited, but higher hydrocarbons such as squalane, liquid paraffin, light liquid paraffin, petrolatum, ceresin wax, microcrystalline wax, squalene, and gelling hydrocarbons; olive oil, jojoba oil, sesame oil, Fats and oils such as soybean oil, cacao butter, camellia oil, peanut oil, beef tallow, lard, triacetin, hydrogenated castor oil; waxes such as beeswax, white beeswax, carnauba wax and lanolin; fatty acids such as stearic acid and oleic acid; lanolin Higher alcohols such as alcohol, myristyl alcohol, cetanol (cetyl alcohol), stearyl alcohol, cetostearyl alcohol and cholesterol; and fatty acid esters such as isopropyl myristate, stearyl myristate and medium-chain fatty acid triglycerides.
• hydrocarbons such as squalane, liquid par
• hydrophilic base examples include, but are not limited to, lower alcohols such as ethanol, propanol and isopropanol; polyhydric alcohols such as glycerin, 1,3-butylene glycol and propylene glycol; sugar alcohols such as sorbitol and mannitol; is mentioned.
• the above bases may be used alone or in combination of two or more.
• wetting agent Humectants keep the skin moist when applying topical preparations.
• Wetting agents include, but are not limited to, vaseline, glycerin, propylene glycol, 1,3-butylene glycol, and the like. The above wetting agents may be used alone or in combination of two or more.
• Thickeners increase the viscosity or gel the topical preparation.
• Thickeners include, but are not limited to, gelatin, agar, carrageenan, gum arabic, tragacanth, sodium alginate, propylene glycol alginate, carboxyvinyl polymer, polyvinyl alcohol (partially saponified), sodium alginate, methylcellulose, carboxymethylcellulose, Water-soluble cellulose derivatives (hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydrophobized hydroxypropylmethylcellulose, etc.), sodium polyacrylate, glycerin monooleate, pectin, xanthan gum and the like.
• the above thickeners may be used alone or in combination of two or more.
• Emulsifiers emulsify topical preparations in oil-in-water (o/w) or water-in-oil (w/o) form.
• Emulsifiers are not particularly limited, but cationic surfactants such as alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyldiethylamine salts, and fatty acid polyamine condensates; polyoxyethylene Anionic surfactants such as alkyl ether phosphates, alkyl sulfates, saturated higher fatty acid salts, N-acyl amino acid salts; sucrose fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene fatty acid esters, polyoxy Nonionic surfactants such as ethylene sorbitan fatty acid ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyethylene glycol, polyethylene
• the emulsifying aid stabilizes the emulsification when the topical preparation is emulsified in oil-in-water (o/w) or water-in-oil (w/o) form.
• emulsifying aids include, but are not limited to, cetanol (cetyl alcohol), stearyl alcohol, oleyl alcohol, isostearyl alcohol, and the like. The above emulsifying aids may be used alone or in combination of two or more.
• Preservatives prevent or suppress contamination and decomposition of external preparations by microorganisms.
• Preservatives include, but are not limited to, parahydroxybenzoic acid, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, sodium benzoate, chlorobutanol, chlorocresol, benzyl alcohol, salicylic acid, phenoxyethanol. , thymol, dibutylhydroxytoluene, sodium edetate hydrate, sodium dehydroacetate, sorbic acid, potassium sorbate, benzalkonium chloride and the like.
• the preservatives mentioned above may be used alone or in combination of two or more.
• Solubilizer increases the solubility of metronidazole in a base or the like.
• solubilizing agent include, but are not particularly limited to, monoalcohols such as ethanol and isopropyl alcohol.
• the above-mentioned solubilizing agents may be used alone or in combination of two or more.
• Stabilizers prevent or inhibit chemical degradation or physical changes of metronidazole.
• stabilizers include, but are not limited to, sodium bisulfite, sodium pyrosulfite, ascorbic acid, tocopherol, dibutylhydroxytoluene, sodium edetate (EDTA), benzotriazole, and the like.
• the stabilizers mentioned above may be used alone or in combination of two or more.
• pH adjuster maintains the stability of metronidazole and prevents or reduces the irritation of external preparations to the body.
• pH adjusters include, but are not limited to, lactic acid, acetic acid, acetates (sodium acetate, etc.), citric acid, citrates (sodium citrate, etc.), phosphoric acid, phosphates (sodium phosphate, etc.), isopropanolamine, triisopropanolamine, triethanolamine, potassium hydroxide, sodium hydroxide and the like.
• the above pH adjusters may be used alone or in combination of two or more.
• the dosage form of the external preparation is not particularly limited as long as it can be applied to the skin (affected area), and includes ointments, creams, gels, lotions and the like.
• Ointment are semi-solid preparations for external use in which an active ingredient is dissolved or dispersed in a base to be applied to the skin, and include oleaginous ointments and water-soluble ointments.
• the external preparation When the external preparation is an oleaginous ointment, it contains a hydrophobic base as a base. In addition, preservatives, stabilizers and the like may be further included as additives.
• Methods for producing oleaginous ointments include, for example, a base melting step of heating and melting a hydrophobic base, an addition step of adding metronidazole, and a mixing step of mixing and dissolving or dispersing metronidazole. manufacturing methods. At this time, in the mixing step, the ingredients are mixed and kneaded until the whole is homogeneous.
• the oleaginous ointment contains an additive, it may be added at any time of the base melting step, the addition step, or the mixing step, but is preferably added at the addition step.
• the external preparation when it is a water-soluble ointment, it contains a water-soluble base as a base.
• a water-soluble base as a base.
• thickeners, preservatives, stabilizers, pH adjusters and the like may be further included.
• a method for producing a water-soluble ointment includes, for example, a base melting step of heating and melting a water-soluble base, an addition step of adding metronidazole, and a mixing step of mixing and dissolving or dispersing metronidazole. manufacturing methods. At this time, in the mixing step, the ingredients are mixed and kneaded until the whole is homogeneous.
• the water-soluble ointment contains additives, they may be added at any time of the base melting step, the addition step, or the mixing step, but are preferably added in the addition step.
• Creams are oil-in-water (o/w) or water-in-oil (w/o) emulsified semi-solid external preparations that are applied to the skin.
• the cream contains, as a base, at least one selected from the group consisting of a hydrophobic base and a hydrophilic base, water and an emulsifier.
• a base at least one selected from the group consisting of a hydrophobic base and a hydrophilic base
• water emulsifier
• emulsifier emulsifier for emulsifier for emulsifier for emulsifier for emulsifier.
• thickeners, emulsifying aids, preservatives, stabilizers, pH adjusters and the like may be further included.
• a hydrophobic base as it is or an additive such as an emulsifier is added to prepare an oil phase component adjustment step, and water is used as it is or an additive such as an emulsifier is added.
• the cream may be added at any time of the oil phase component preparation step, the water phase component preparation step, and the emulsification step, but the oil phase component preparation step and/or the water phase component It is preferably added during the preparation process.
• Gels are gel-like external preparations that are applied to the skin, and include aqueous gels and oily gels.
• Aqueous gels contain water as a base. Moreover, at least one selected from the group consisting of an inorganic hydrogel-suspending base, an organic hydrogel-suspending base, and a lyogel-suspending base may be included as a base. Further, as additives, a thickener, a preservative, a wetting agent, a stabilizer, a pH adjuster, and the like may be further included.
• Examples of methods for producing aqueous gels include production methods including an addition step of adding metronidazole to water to dissolve or suspend it, and a gelation step of gelling. At this time, when the aqueous gelling agent contains an additive, it may be added at any point of the adding step or the gelling step.
• preservatives, wetting agents, stabilizers, and pH adjusters are preferably added in the adding step, and thickeners are preferably added in the gelling step.
• the oily gel contains a water-soluble base as a base. Moreover, at least one selected from the group consisting of an inorganic hydrogel-suspending base, an organic hydrogel-suspending base, and a lyogel-suspending base may be included as a base. Further, as additives, a thickener, a preservative, a wetting agent, a stabilizer, a pH adjuster, and the like may be further included.
• Examples of methods for producing an oily gel include a production method including an addition step of adding metronidazole to a water-soluble base and dissolving or suspending it, and a mixing step of mixing. At this time, when the oily gel contains an additive, it may be added at any point of the addition step or the mixing step, but it is preferable to add it in the addition step.
• Lotions are liquid topical preparations in which metronidazole is dissolved or dispersed in an aqueous solution.
• a lotion contains water as a base.
• an emulsion lotion containing at least one selected from the group consisting of a hydrophobic base and a hydrophilic base as a base and emulsified with an emulsifier can also be used.
• thickeners, emulsifying aids, preservatives, stabilizers, pH adjusters and the like may be further included.
• Examples of methods for producing lotions include production methods including an addition step of adding metronidazole to a base such as water to dissolve or finely disperse it, and a mixing step of mixing. At this time, in the mixing step, the ingredients are mixed until the whole is homogeneous.
• the lotion may be added at any point of the addition process or the mixing process, but it is preferable to add it in the addition process.
• the dosage form of the external preparation is preferably a gel, more preferably an aqueous gel, and particularly preferably a gel containing a wetting agent. It is preferable that the dosage form of the external preparation is a gel, since it is less irritating and easier to apply to sensitive or inflamed skin. In addition, it is preferable that the external preparation is in the form of a water-based gel from the viewpoint that it can be easily applied to the affected area and that the application site is inconspicuous even when applied to the face.
• the external preparation is an aqueous gel containing metronidazole and at least one additive selected from the group consisting of carboxyvinyl polymer, propylene glycol, and sodium edetate (EDTA).
• carboxyvinyl polymer as a thickener, it is possible to obtain a stable gel agent with little change in quality over time and temperature-induced viscosity change.
• propylene glycol as a humectant, irritation to the application site is reduced, and treatment can be continued for the required period of time.
• sodium edetate (EDTA) as a stabilizer, the carboxyvinyl polymer can be protected from metal cations, and a decrease in the viscosity of the gel can be suppressed.
• the external preparation according to the present invention is applied to the affected area twice a day. Application times are preferably in the morning (6-12 hours, preferably 7-9 hours) and in the evening (18-24 hours, preferably 19-22 hours). In addition, it is preferable to apply the topical agent according to the present invention after washing the face or taking a bath.
• the affected area to which the topical preparation of the present invention is applied is not particularly limited, but is usually a site with inflammatory eruptions (papules/pustules) and erythema on the entire face.
• the external preparation according to the present invention is preferably applied continuously for at least 2 weeks, more preferably continuously applied for at least 8 weeks, and further preferably continuously applied for at least 12 weeks.
• Continuous application of topical agents for at least two weeks can reduce the number of inflammatory acne lesions and erythema severity early on.
• continuous application of the topical agent for at least 8 weeks can further reduce the number of inflammatory acne lesions and erythema severity over time.
• continuous application of the topical agent for at least 12 weeks can result in a greater reduction in the number of inflammatory acne lesions and erythema severity compared to after 8 weeks.
• the administration period of the external preparation is preferably 2 to 14 weeks, more preferably 8 to 13 weeks, even more preferably 10 to 12 weeks, and preferably 12 weeks. Especially preferred.
• topical preparation it is preferable to continue applying the topical preparation according to the present invention even when inflammatory acne lesions (papules/pustules) and erythema on the entire face are reduced or eliminated (rosacea is remissioned). For example, even if a patient with an IGA score of 4 has an IGA score of 0 or 1 due to the application of the topical preparation, it is preferable to continue applying the topical preparation. After the inflammatory eruptions (papules/pustules) and erythema on the whole face have been reduced or disappeared (rosacea is remissioned), topical preparations should be applied to the affected areas with inflammatory eruptions (papules/pustules) and erythema.
• the duration is preferably at least 2 weeks, more preferably at least 8 weeks, even more preferably at least 12 weeks. In one preferred embodiment, said duration is preferably 2 to 14 weeks, more preferably 8 to 13 weeks, even more preferably 10 to 12 weeks, particularly preferably 12 weeks.
• topical preparations exhibit therapeutic effects when used alone, but may be combined with other therapeutic agents or other therapeutic methods.
• the above-mentioned other therapeutic agent means a therapeutic agent other than the therapeutic agent using the above-mentioned externally applied agent, and includes other externally applied agents and internal medicines.
• the above-mentioned other external agents mean external agents other than the external agent according to the present invention, and include ivermectin, azelaic acid, brimonidine, oxymetazoline, sulfur sulfacetamide, and the like.
• the oral medicine is not particularly limited, but includes vitamin A derivatives such as isotretinoin; tetracycline antibiotics such as minocycline and doxycycline; macrolide antibiotics such as erythromycin and azithromycin.
• vitamin A derivatives such as isotretinoin
• tetracycline antibiotics such as minocycline and doxycycline
• macrolide antibiotics such as erythromycin and azithromycin.
• the above-mentioned other therapeutic agents may be used in combination of two or more.
• external preparations and combination drugs with other therapeutic agents are provided.
• the topical agent and the other therapeutic agent may be administered simultaneously or sequentially.
• the other treatment methods include, but are not particularly limited to, treatment methods using surgical means.
• Treatment methods using the surgical means include laser treatment, IPL (Intense Pulsed Light) treatment, PDT (Photo Dynamic Therapy), phototherapy, electrocoagulation, dermabrasion, chemical peeling, and the like. mentioned. These therapeutic methods using surgical means may be used alone or in combination of two or more.
• a combination therapy of a treatment method using an external preparation and a treatment method using a surgical means is provided.
• a combination therapy of the treatment method using the external preparation, the treatment method using the internal medicine, and the treatment method using surgical means is provided.
• ⁇ Treatment method> there is provided a method for treating at least one skin lesion selected from the group consisting of papules, pustules, and erythema in rosacea patients with an IGA (Investigator Global Assessment) score of 4.
• the treatment method includes applying an external preparation containing metronidazole to the affected area twice a day. Specific administration methods are as described above.
• Example 1 (External agent) As an external preparation, metronidazole (0.75% by mass) as an active ingredient, water as a base, carboxyvinyl polymer as a thickener, methyl parahydroxybenzoate and propyl parahydroxybenzoate as preservatives, An aqueous gel containing propylene glycol as a wetting agent, sodium edetate hydrate as a stabilizer, and sodium hydroxide as a pH adjuster and having a viscosity of 15,000 to 45,000 mPa was used. .
• Placebo water as base, carboxyvinyl polymer as thickening agent, methyl parahydroxybenzoate and propyl parahydroxybenzoate as preservatives, propylene glycol as wetting agent, and edetic acid as stabilizer.
• a gel external preparation containing sodium hydrate and sodium hydroxide as a pH adjuster was used. That is, the placebo does not contain the active ingredient, metronidazole.
• IGA score The patient's IGA score was judged according to the following criteria.
• Small papules localized, palpable raised changes ⁇ 5 mm in diameter
• Major papules localized, palpable raised changes greater than 5 mm in diameter and ⁇ 10 mm
• Small pustules canopy-encapsulated skin protuberances ⁇ 5 mm in diameter with purulent (mainly neutrophil) content (white to yellow)
• Large pustule Canopy-encapsulated skin protuberance >5 mm to 10 mm in diameter with purulent (predominantly neutrophilic) content (white to yellow)
• topical agent or placebo In each patient, an appropriate amount of the topical agent or placebo was applied to the inflammatory eruptions (papules/pustules) and erythema on the entire face twice a day, morning and night, after washing the face or after bathing. At this time, the topical agent or placebo was administered continuously for 12 weeks regardless of the therapeutic effect. When the inflammatory eruption and erythema disappeared, the topical agent or placebo was continuously applied to the site where the inflammatory eruption and erythema were present.
• the number of inflammatory acne lesions and the severity of erythema in each patient were evaluated again. Then, the percentage change score of the number of inflammatory acne lesions and the change score of erythema severity were calculated according to the following criteria. Then, the percentage of patients in each group whose change score for the number of inflammatory acne lesions and change score for erythema severity were both 3 or more was calculated.

Landscapes

• Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Dermatology (AREA)
• Epidemiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (2)

Applications Claiming Priority (1)

Publications (1)

Family

ID=84544288

Family Applications (1)

Country Status (2)

Citations (4)

• 2021
  • 2021-06-21 JP JP2023529196A patent/JPWO2022269665A1/ja active Pending
  • 2021-06-21 WO PCT/JP2021/023336 patent/WO2022269665A1/ja not_active Ceased

Patent Citations (4)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events