WO2021177257A1 - Procédé de traitement de l'hyperhidrose axillaire primaire et produit pharmaceutique associé - Google Patents

Procédé de traitement de l'hyperhidrose axillaire primaire et produit pharmaceutique associé Download PDF

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WO2021177257A1
WO2021177257A1 PCT/JP2021/007791 JP2021007791W WO2021177257A1 WO 2021177257 A1 WO2021177257 A1 WO 2021177257A1 JP 2021007791 W JP2021007791 W JP 2021007791W WO 2021177257 A1 WO2021177257 A1 WO 2021177257A1
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treatment
preparation
hyperhidrosis
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Inventor
信之 小寺
俊之 萬屋
幹樹 赤松
一平 大谷
弘 伊関
明大 小野
大樹 坪井
勇希 西原
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Kaken Pharmaceutical Co Ltd
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Kaken Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • 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
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    • 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
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    • 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
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a method for treating primary axillary hyperhidrosis and a pharmaceutical preparation containing a sofpironium bromide for treating, treating, or preventing primary axillary hyperhidrosis.
  • Hyperhidrosis is a large amount of sweating on the palms and soles caused by heat, mental stress, or other causes, which interferes with daily life (for example, documents and notes are torn by sweat, and sweat is a concern. It is a state in which you cannot hold hands with others, you need to change your underwear many times a day, your mobile phone gets wet with sweat and breaks, etc.), which significantly reduces QOL (Non-Patent Document 1).
  • Human sweat glands include eccrine sweat glands and apocrine sweat glands, and the sweat that causes hyperhidrosis is secreted from the eccrine sweat glands (Non-Patent Document 2).
  • Eccrine sweat glands are regulated by cholinergic nerves, and acetylcholine is thought to induce sweating by stimulating M3 type muscarinic receptors located in the postsynaptic membrane of the nerves that control eccrine sweat glands (non-patented). Document 3).
  • Hyperhidrosis is classified into systemic hyperhidrosis and local hyperhidrosis depending on whether the onset site is systemic or part of the body, and local hyperhidrosis often occurs in the palms, soles, and axilla. In addition, it is classified into primary disease with no particular cause and secondary disease caused by complications with other diseases (drug-induced or cardiovascular disease in the systemic system, peripheral neuropathy in the local area, etc.) depending on the pathogenesis. From the above, primary axillary hyperhidrosis can be defined as a condition in which a large amount of sweating occurs in the axilla regardless of a specific cause and interferes with daily life.
  • the severity and therapeutic effect of primary hyperhidrosis are based on subjective symptoms in the following four stages: (1) sweating is not a concern at all and does not interfere with daily life; (2) sweating can be tolerated. However, there are occasional problems with daily life; (3) sweating is almost unbearable and frequently interferes with daily life; (4) sweating is unbearable and always interferes with daily life. It can be judged according to the Disease Severity Scale (HDSS, Strutton et al.). In HDSS, the judgment is made based on the above 4 scores (1) to (4), but since (3) and (4) are considered as severe indicators, the following specification also includes severe primary hyperhidrosis. Hyperhidrosis may refer to the pathology of HDSS scores (3) and (4). In addition, sweating amount measurement such as iodine paper method and weight measurement method is also used for determining the severity and therapeutic effect (Non-Patent Document 1).
  • Non-Patent Document 4 the prevalence of primary axillary hyperhidrosis in Japan is 5.75%, and the average age of onset is 19.5. I'm old. Of these, the rate of consultations with medical institutions for patients with primary local hyperhidrosis, including axillary hyperhidrosis, was 6.3%, and 47.8% of all patients used non-antiperspirant deodorants, which is appropriate. It is a disease that requires the development of a proper treatment environment and awareness of patients.
  • Non-Patent Document 1 the first choice for the treatment of primary axillary hyperhidrosis is simple topical or occlusive dressing (ODT) of aluminum chloride. If this does not work, the second option is intradermal administration of botulinum toxin type A (50 units of Botox® injection).
  • Other options may include surgical therapies such as Endoscopic thoracic sympathectomy (ETS), nerve block, laser therapy, oral anticholinergic therapy, and psychotherapy.
  • ETS Endoscopic thoracic sympathectomy
  • Surgical therapy such as ETS is an irreversible treatment and cannot be easily applied clinically because compensatory sweating that causes abnormal sweating from other sites may occur.
  • Oral therapy with anticholinergic agents causes systemic side effects such as dry mouth, drowsiness, and nausea due to anticholinergic action.
  • Provansign® Tablets 15 mg, which has insurance coverage for hyperhidrosis in Japan, thirst (about 30%), constipation (about 12%), dysuria (about 9%), eyes The frequency of dysuria (about 9%) is relatively high.
  • Oral anticholinergic therapy may not be available in sufficient efficacy due to these side effects.
  • existing treatment methods have problems with invasive and systemic side effects, and there is a need for a drug capable of avoiding these problems.
  • acetylcholine is known as one of the main neurotransmitters in the living body and has various pharmacological actions, and the sweating action by activation of sweat glands is one of them. Therefore, anticholinergic agents are useful in the treatment of hyperhidrosis by inhibiting the action of acetylcholine. Furthermore, by applying an anticholinergic agent externally, side effects associated with oral administration can be alleviated. In addition, side effects that may occur with existing treatments, such as the onset of irritant dermatitis in topical aluminum chloride therapy, or pain during injection when botulinum toxin is administered, and transient muscle weakness, etc. Side effects can be avoided.
  • Soft glycopyrrolate is a derivative of glycopyrrolate, which is an anticholinergic agent, and one of the typical soft glycopyrrolate is sofpironium bromide.
  • the sofpironium bromide has the following formula (I): It is an ester compound represented by (hereinafter, may be referred to as “BBI-4000” or “compound (I)”) and is a bromide salt of quaternary ammonium. So far, an external application preparation of sofpironium bromide and a method for treating hyperhidrosis using the same have been reported.
  • Patent Document 1 discloses that soft glycopyrrolate can be used for the treatment of hyperhidrosis.
  • Patent Document 2 suggests the therapeutic effect of BBI-4000 when applied topically in a subject with axillary hyperhidrosis.
  • Patent Documents 3 and 4 show the safety of locally applied BBI-4000 and its effect on sweat production in subjects with hyperhidrosis (BBI-4000-CL-101 study).
  • one of the problems to be solved by the present invention is to provide a clinically effective pharmaceutical preparation containing sofpironium bromide as an active ingredient and for external application.
  • Another problem to be solved by the present invention is to provide a method for using a clinically effective pharmaceutical preparation containing sofpironium bromide as an active ingredient for external application according to the severity.
  • One of yet another problems to be solved by the present invention is to provide an effective therapeutic agent or treatment method for primary axillary hyperhidrosis in which the total sweating weight of both axillae for 5 minutes before treatment is 100 mg or more. That is.
  • One of the other problems to be solved by the present invention is an effective therapeutic agent or treatment method for severe primary axillary hyperhidrosis in which the total sweating weight of both axillae for 5 minutes before treatment is 400 mg or more.
  • one of the still another problems to be solved by the present invention is to provide a therapeutic agent or a therapeutic method effective for primary axillary hyperhidrosis and which can be administered for a long period of time.
  • the present inventors have applied the pharmaceutical preparation of sofpironium bromide to both axillas once a day with an HDSS score of 3 or 4. Revealed clinical usefulness for some severe primary axillary hyperhidrosis and / or primary axillary hyperhidrosis with a total axillary sweating weight of 100 mg or more for 5 minutes prior to treatment bottom.
  • the present inventors are clinically extremely sensitive to severe primary axillary hyperhidrosis in which the pharmaceutical product has a total sweating weight of both axillae of 400 mg or more for 5 minutes before treatment. It turned out to be useful.
  • the present invention includes pharmaceutical formulations of sofpironium bromide for the treatment, treatment, or prevention of primary hyperhidrosis. Furthermore, the present invention includes a method for treating, treating, or preventing primary hyperhidrosis using a pharmaceutical preparation of sofpironium bromide.
  • the present invention includes the following inventions.
  • a pharmaceutical preparation containing sofpironium bromide as an active ingredient and applied to both axillas once a day, and the total sweating weight of both axillas by a weight measurement method for 5 minutes before treatment is 400 mg or more.
  • the primary axillary hyperhidrosis is severe primary axillary hyperhidrosis with an HDSS score of 3 or 4 before treatment, and the HDSS score at the end of treatment is improved to 1 or 2 and the treatment is performed.
  • [17] A method of treating or treating severe primary axillary hyperhidrosis with a pretreatment HDSS score of 3 or 4. a) Applying a pharmaceutical product containing sofpironium bromide as an active ingredient to both axillas once a day, b) The HDSS score at the end of treatment is improved to 1 or 2, and the ratio of the total sweat weight of both axillae at the end of treatment to the total sweat weight of both axilla before treatment is improved to 0.5 or less. ,Method. [18] The method according to [17] above, for treating primary axillary hyperhidrosis in which the total sweating weight of both axillae by a 5-minute weight measurement method before treatment is 400 mg or more. [19] The method according to [17] or [18] above, wherein the pharmaceutical preparation of sofpironium bromide is administered once a day for a treatment period of at least 6 weeks.
  • a pharmaceutical preparation of sofpironium bromide can be used for the treatment of primary axillary hyperhidrosis in which the total sweating weight of both axillae is 100 mg or more for 5 minutes before treatment, and in particular, 5 before treatment. It can be used to treat severe primary axillary hyperhidrosis with a total axillary sweating weight of 400 mg or more per minute.
  • Test Example 1 This is a time course for a confirmatory study of BBI-4000 in patients with primary axillary hyperhidrosis.
  • * 1 baseline includes 3 times of baselines 1 to 3
  • * 2 includes 3 times of 1 to 3 at the 6th week of administration at the end of treatment.
  • Test Example 2 This is a time course of a long-term administration study of BBI-4000 in patients with primary axillary hyperhidrosis.
  • the preparation of the present invention is an external pharmaceutical preparation for topical administration containing sofpironium bromide as an active ingredient.
  • the disease to be treated, treated and / or prevented is hyperhidrosis, preferably primary hyperhidrosis, more preferably primary local hyperhidrosis, and even more.
  • Preferred is primary axillary hyperhidrosis.
  • the pharmaceutical product of the present invention is administered once a day, and preferably an appropriate amount is locally applied once a day.
  • the preparation of the present invention is preferably applied to both axilla and palm. It is an external preparation for use.
  • the preparation of the present invention can also be applied to the one-sided axilla or one-sided palm.
  • the formulations of the invention are formulated at 6-48 hour intervals, 8-36 hour intervals, 12-36 hour intervals, 20-28 hour intervals, or 22-26 hour intervals. Be administered.
  • the pharmaceutical product of the present invention is administered before bedtime.
  • the pharmaceutical product of the present invention is administered once daily before bedtime.
  • the formulations of the invention are 6-48 hour intervals, 8-36 hour intervals, 12-36 hour intervals, 20-28 hour intervals, or 22-28 hours prior to bedtime. It is administered at intervals of 26 hours.
  • sweating weight is measured by a weight measuring method.
  • a weight measuring method generally, a method of adhering filter paper or gauze to the axilla for a certain period of time and measuring the sweating weight thereof can be adopted.
  • a typical weight measurement method involves attaching a pre-weighed filter paper to both axillary sockets of a subject for 5 minutes, measuring the weight, and taking a difference from the tare weight. One or two or more steps may be omitted, or one or two or more additional steps may be added as required.
  • “sweat weight” refers to a measured value, which is a measured value for 5 minutes by the sweating weight measuring method unless otherwise specified.
  • the treatment period using the pharmaceutical product of the present invention is not particularly limited as long as the effects of the present invention are exhibited.
  • the pharmaceutical product of the present invention is characterized in that its efficacy and safety are ensured even after long-term administration.
  • the treatment period using the formulation of the present invention is 2 weeks, 4 weeks, 6 weeks, 12 weeks, 24 weeks, 36 weeks, 48 weeks, 52 weeks, 2 years, or 3 More than a year.
  • the administration period of the pharmaceutical product of the present invention is at least 6 weeks, at least 12 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, or at least 52 weeks.
  • the duration of treatment with the formulations of the invention is in the range of 6 to 24 weeks, 6 to 36 weeks, 6 to 48 weeks, or 6 to 52 weeks.
  • the treatment period using the formulation of the present invention is a period of more than 6 weeks, a period of more than 6 weeks and up to 24 weeks, a period of more than 6 weeks and up to 36 weeks, 6 The period is more than a week and up to 48 weeks, or more than 6 weeks and up to 52 weeks.
  • the content of the sofpironium bromide contained in the formulation of the present invention is not particularly limited, but is preferably 1 w / w% to 30 w / w%, more preferably 1 w / w% to 20 w / w%, and even more preferably. Is from 5w / w% to 15w / w%.
  • the preferred content of sofpironium bromide is 5 w / w%, 10 w / w%, or 15 w / w%, particularly preferably 5 w / w%, based on the total amount of the drug. ..
  • the range is described as "A to B" or "A to B"
  • the numerical value at the end thereof is also included unless otherwise specified.
  • the average amount of the pharmaceutical preparation of sofpironium bromide per axillary administration is preferably 0.1 mL to 2.0 mL, more preferably 0.5 mL to 1.0 mL, and further preferably 0.6. From mL to 0.7 mL.
  • the average amount of a single dose of the active ingredient (sofpironium bromide) applied per 1 cm 2 of the axillary body surface is preferably 1.0 ⁇ g to 5000 ⁇ g, more preferably 5.0 ⁇ g to 2000 ⁇ g. , More preferably 10 ⁇ g to 1000 ⁇ g, and even more preferably 100 ⁇ g to 1000 ⁇ g.
  • a single-use dose of the pharmaceutical product of the present invention is received by an applicator or the like, and the propellant or the like is pressed against the axilla to apply the pharmaceutical product in a single dose to the axilla.
  • the applicator or the like as described above, a predetermined amount can be appropriately administered to the axilla, and the pharmaceutical product does not easily adhere to the operating hand, etc., so that contamination does not occur and the user can use it. It is beneficial.
  • the coating tool used with the formulation of the present invention is separably connected to the container body for storing the formulation.
  • the coating tool used with the formulation of the invention is inseparably connected to the container body in which the formulation is stored.
  • a discharge hole for discharging the pharmaceutical product from the container body may be provided at the center of the application surface of the coating tool.
  • the preparation of the present invention is a gel preparation or an external liquid preparation having a medium viscosity.
  • the medium viscosity refers to a viscosity of 100 mPa ⁇ s to 2000 mPa ⁇ s (25 ° C), and in a narrow sense, refers to a viscosity of 100 mPa ⁇ s to 1100 mPa ⁇ s (25 ° C).
  • the viscosity of the pharmaceutical product of the present invention is preferably 100 mPa ⁇ s to 900 mPa ⁇ s (25 ° C.), more preferably 250 mPa ⁇ s to 850 mPa ⁇ s (25 ° C.). Since the pharmaceutical product of the present invention can be administered for a long period of time, it is preferable that the viscosity is maintained for a long period of time.
  • a sofpironium bromide preparation containing 0.015 w / w% to less than 0.1 w / w%, 0.015 w / w% to 0.075 w / w%, or 0.05 w / w% anhydrous citric acid has a long-term viscosity. Retained.
  • the present invention is a method for administering a preparation containing sofpironium bromide to a human, and includes a novel method for treating, treating, or preventing primary hyperhidrosis, axillary hyperhidrosis, particularly primary axillary hyperhidrosis. ..
  • the present invention comprises a pharmaceutically acceptable formulation containing 1 w / w% to 15 w / w% sofpironium bromide, more preferably 5 w / w% sofpironium bromide, once daily for a treatment period of at least 6 weeks. , Includes methods of application to both axillae.
  • “decreasing the HDSS score by 1 or more” means that the HDSS score decreases by 1 or more before and after a certain treatment period, for example, a subject whose HDSS score was 3 before the treatment. HDSS score of 2 or 1 during or after treatment. It also means, for example, that the HDSS score of a subject whose HDSS score was 4 before treatment becomes either 3 to 1 during or after treatment.
  • the pharmaceutical product of the present invention is characterized by having an antiperspirant effect that lowers the HDSS score by at least one during or after the treatment as compared with before the treatment.
  • the formulations of the invention are therapeutic agents for severe primary axillary hyperhidrosis with a pretreatment HDSS score of 3 or 4 and are during or during treatment as compared to pretreatment. It is characterized by having an antiperspirant effect that lowers the HDSS score by 1 or more after treatment.
  • the formulations of the invention are therapeutic agents for severe primary axillary hyperhidrosis with a pretreatment HDSS score of 3 or 4 and an HDSS score of 1 during or after treatment. Or it is characterized by improving to 2.
  • the formulations of the invention are therapeutic agents for severe primary axillary hyperhidrosis with a pretreatment HDSS score of 3 or 4 and an HDSS score of 1 or 1 during or after treatment. It is characterized by improvement to 2 and the ratio of the total sweating weight of both axillae at the end of treatment to 0.5 or less of the total sweating weight of both axillae before treatment.
  • the preparation of the present invention is used during the treatment period or during the treatment period in primary axillary hyperhidrosis in which the total sweating weight of both axillae before treatment is 100 mg / 5 min or more as compared with before the treatment. It is characterized by having an antiperspirant effect that lowers the HDSS score by 1 or more after treatment.
  • the formulations of the invention have a pretreatment HDSS score of 3 or 4 in primary axillary hyperhidrosis with a total pretreatment axillary sweating weight of 100 mg / 5 min or greater. It is a therapeutic agent for severe primary axillary hyperhidrosis, and is characterized by having an antiperspirant action that lowers the HDSS score by 1 or more as compared with before the treatment during or after the treatment.
  • the formulations of the invention have a pretreatment HDSS score of 3 or 4 in primary axillary hyperhidrosis with a total pretreatment axillary sweating weight of 100 mg / 5 min or greater.
  • a therapeutic agent for severe primary axillary hyperhidrosis characterized in that the HDSS score improves to 1 or 2 during or after treatment.
  • the formulations of the invention have a pretreatment HDSS score of 3 or 4 in primary axillary hyperhidrosis with a pretreatment total axillary sweating weight of 100 mg / 5 min or greater.
  • the formulations of the invention can be used during treatment or during primary axillary hyperhidrosis, where the total sweating weight of both axillae before treatment is 400 mg / 5 min or more, as compared to before treatment. It is characterized by having an antiperspirant effect that lowers the HDSS score by 1 or more after treatment.
  • the formulations of the invention have a pretreatment HDSS score of 3 or 4 in primary axillary hyperhidrosis with a total pretreatment axillary sweating weight of 400 mg / 5 min or greater. It is a therapeutic agent for severe primary axillary hyperhidrosis, and is characterized by having an antiperspirant action that lowers the HDSS score by 1 or more as compared with before the treatment during or after the treatment.
  • the formulations of the invention have a pretreatment HDSS score of 3 or 4 in primary axillary hyperhidrosis with a total pretreatment axillary sweating weight of 400 mg / 5 min or greater.
  • a therapeutic agent for severe primary axillary hyperhidrosis characterized in that the HDSS score improves to 1 or 2 during or after treatment.
  • the formulations of the invention have a pre-treatment HDSS score of 3 or 4 in primary axillary hyperhidrosis with a pre-treatment total axillary sweat weight of 400 mg / 5 min or greater.
  • the pharmaceutical product of the present invention may require a step of wiping off sweat, water, and dirt on the treatment site before administering the pharmaceutical product of the present invention.
  • a randomized, double-blind, parallel-group comparison of patients with primary axillary hyperhidrosis showed a topical drug containing sofpironium bromide (sofpironium bromide 5w / w%, hydroxypropyl cellulose 1.25w / w%, isopropyl myristate).
  • sofpironium bromide sofpironium bromide 5w / w%, hydroxypropyl cellulose 1.25w / w%, isopropyl myristate.
  • anhydrous citrate 0.05w / w%, hexylene glycol 10w / w%, and the balance is composed of anhydrous ethanol is applied to the axilla once a day for 6 weeks before going to bed.
  • the superiority of the efficacy to the placebo preparation was verified.
  • the primary endpoint is the proportion of subjects with an HDSS score of 1 or 2 at the end of treatment and a ratio of total axillary sweat weight at the
  • before treatment refers to a time point prior to treatment by administration of a pharmaceutical preparation of sofpironium bromide.
  • at the end of treatment refers to the time of visit, which is the standard for the end of treatment. At the end of treatment, it consists of three visit dates after the prescribed administration period, and the HDSS score and sweat weight at the end of treatment refer to the median values unless otherwise noted.
  • measuring treatment refers to the period between the start of treatment and the end of treatment.
  • baseline refers to each measurement value regarding the degree of reference symptoms before administration. Baseline is measured for a specified period of time prior to administration.
  • the baseline HDSS score and sweat weight in this study example refer to the median of each measurement on three visits within 9 days, defined as baseline 1, baseline 2, and baseline 3.
  • the number of days of administration of the pharmaceutical preparation of sofpironium bromide is the number of days with baseline 3 as the first day, and expressions such as "administration period” and "administration week” also conform to this standard.
  • Baseline 3 is the day when the pharmaceutical preparation of sofpironium bromide is started. Figure 1 shows the time course of this test.
  • Sweat weight The median value of the total sweating weight of both axillae at baselines 1 to 3 is taken as the baseline sweating weight, and the median value of the total sweating weight of both axillae at 6 weeks after administration is used as both at the end of treatment.
  • the total axillary sweating weight was used.
  • Basic statistics for the total sweating weight of both axillas were calculated for each administration group and compared between the administration groups. In addition, the following was calculated, the confidence intervals were shown for the differences between the administration groups, and statistical tests were performed.
  • HDSS -Percentage of subjects whose ratio of total axillary sweat weight to baseline at the end of treatment was 0.5 or less-Amount of change in total axillary sweat weight from baseline at the end of treatment 2
  • the median HDSS score of baselines 1 to 3 was defined as the baseline HDSS score, and the median HDSS score of 1 to 3 weeks 6 weeks of administration was defined as the HDSS score at the end of treatment. It was tabulated for each administration group and for each implementation period. We also calculated the proportion of subjects with an HDSS score of 1 or 2 at the end of treatment, showed confidence intervals for differences between treatment groups, and performed statistical tests.
  • Sweat weight measurement 1 Measurement conditions ⁇ Room temperature: 20 ° C to 28 ° C, humidity: 20% RH to 80% RH 2) Measurement method A filter paper whose weight was measured in advance was attached to both axillae of the subject for 5 minutes. After that, the sweating weight was calculated by measuring the weight of the paper containing sweat. In addition, each subject was conducted in the range of 8:00 am to 7:00 pm at a time when the difference between the implementation periods did not exceed 4 hours.
  • ⁇ Target patients and main inclusion criteria Patients with primary axillary hyperhidrosis who are 12 years of age or older at the time of consent and meet the following diagnostic criteria and conditions 1. Patients diagnosed with primary axillary hyperhidrosis who meet 2 or more of the following 6 items by interview in screening (1) The first symptoms were under 25 years old (2) Sweating is seen symmetrically (3) Sweating stops during sleep (4) There is an episode of hyperhidrosis at least once a week (5) Family history can be seen (6) Excessive sweating interferes with daily life 2. Patients who meet all of the following conditions (1) HDSS score of 3 or 4 at each of baselines 1 to 3 (2) At any two of the three baselines 1-3, the sweating weight of each axilla is 50 mg or more.
  • ⁇ Main exclusion criteria> 1. Patients with secondary hyperhidrosis 2. Patients with hyperhidrosis symptoms that start or worsen due to menopause 3. Patients who are indicated for thoracic sympathetic nerve blockade
  • the percentage of subjects who showed efficacy was 36.4% (51/140) in the 0% group, 53.9% (76/141) in the 5% group, and 17.5% (95) in the 5% group than in the 0% group.
  • % Confidence interval: 6.02 to 28.93) High, with statistically significant differences between treatment groups (chi-square test: p 0.003).
  • the primary endpoint "Proportion of subjects with an HDSS score of 1 or 2 at the end of treatment and a ratio of total axillary sweat weight to baseline at end of treatment of 0.5 or less," was 0% in all categories. It was higher in the 5% group than in the group. The difference between the groups was 15.5% in the category of 100 mg or more and less than 400 mg, and 46.2% in the category of 400 mg or more. That is, the difference between groups was larger in the category of 400 mg or more.
  • Test Example 2 Long-term administration study of BBI-4000 in patients with primary axillary hyperhidrosis 5% BBI- in Japanese patients with primary axillary hyperhidrosis, including subjects who participated in the above verification study (Test Example 1) The safety and efficacy of 4000 (same as Test Example 1) administered once daily for 52 weeks before bedtime were examined. The study design was uncontrolled and open.
  • the proportion of subjects with an HDSS score of 1 or 2 52 weeks after transition from Test Example 1 and a ratio of total axillary sweat weight to baseline in Test Example 1 of 0.5 or less was 0% / 5% group 57.4. % (54/94 people), 5% / 5% group 58.2% (53/91 people). Furthermore, the proportion of subjects with an HDSS score of 1 or 2 52 weeks after transition from Test Example 1 was 76.6% (72/94) in the 0% / 5% group and 71.4% (65 /) in the 5% / 5% group. 91 people).
  • the proportion of subjects whose ratio of total axillary sweat weight to baseline at 52 weeks after transition from Test Example 1 was 0.5 or less was 0% / 5% group 66.6% (62/94 subjects), 5% / 5%. It was 67.0% (61/91 people) in the group.
  • the mean ⁇ standard deviation of the change in total axillary sweat weight from baseline at 52 weeks after transition from Test Example 1 was 0% / 5% group -157.7 ⁇ 178.08 mg, 5% / 5% group -141.6. It was ⁇ 168.47 mg.
  • ⁇ Viscosity measurement method> The viscometer was set at 25 ° C., 10 rpm per minute, and the preheat time: 30 seconds, and the value after rotating about 1 mL with a cone rotor: R-H 1 ° 34'x R24 for 200 seconds was measured (Japanese Pharmacopoeia). The second method of measuring the viscosity of the square).
  • Example 5 Example 6, Comparative Example 2 and Comparative Example 3 in the table below were prepared in the same manner as in Test Example 3 and used for various tests.
  • the compounded components were stirred and dissolved in absolute ethanol so as to have the constituents and concentrations in the table to obtain a preparation.
  • the contents of each pharmaceutical product manufactured by this method are shown in the table below.
  • Comparative Example 2 and Comparative Example 3 having an anhydrous citric acid concentration of 0.001 w / w% had a pH of 6.1 to 5.9 at the time of preparation, and the pH fluctuated with time when stored at room temperature.
  • the formulation of Comparative Example 3 having an anhydrous citric acid concentration of 0.001 w / w% significantly decreased in viscosity (-76%) when stored at room temperature for 12 months.
  • the pH after preparation was maintained at 5.2 or less, and the change in viscosity with time was slight.
  • the sofpironium bromide preparation whose pH is maintained at 5.2 or less after the liquid is prepared can suppress the decrease in viscosity with time.
  • this test revealed that when the preparation is stored at room temperature, the preparation having a pH of 2.5 to 5.2 at any time up to 6 months after the liquid preparation is preferable.
  • the preparation having a pH in the range of 2.5 to 5.2 at 1 month, 3 months, or 6 months after preparation is preferable.
  • primary axillary hyperhidrosis in which the total sweating weight of both axillae before treatment with a pharmaceutical preparation of sofpironium bromide is 100 mg or more, particularly severe cases in which the total sweating weight of both axillae before treatment is 400 mg or more. It can be used to treat primary axillary hyperhidrosis.

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Abstract

L'invention concerne une préparation pharmaceutique destinée à être appliquée une fois par jour aux aisselles et comprenant du bromure de sofpironium en tant que principe actif, la préparation étant destinée à traiter l'hyperhidrose axillaire primaire, la production de sueur gravimétrique axillaire bilatérale globale mesurée selon le procédé gravimétrique pendant cinq minutes avant le traitement étant supérieure ou égale à 400 mg.
PCT/JP2021/007791 2020-03-03 2021-03-02 Procédé de traitement de l'hyperhidrose axillaire primaire et produit pharmaceutique associé Ceased WO2021177257A1 (fr)

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