WO2021177257A1 - Method for treating primary axillary hyperhidrosis and pharmaceutical product therefor - Google Patents
Method for treating primary axillary hyperhidrosis and pharmaceutical product therefor Download PDFInfo
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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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- hyperhidrosis
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- 230000036617 axillary hyperhidrosis Effects 0.000 title claims abstract description 73
- 239000000825 pharmaceutical preparation Substances 0.000 title claims abstract description 46
- 229940127557 pharmaceutical product Drugs 0.000 title claims description 22
- 238000000034 method Methods 0.000 title abstract description 29
- 238000011282 treatment Methods 0.000 claims abstract description 143
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- FIAFMTCUJCWADZ-WVXMCOPUSA-M [(1r,3r)-1-(2-ethoxy-2-oxoethyl)-1-methylpyrrolidin-1-ium-3-yl] (2r)-2-cyclopentyl-2-hydroxy-2-phenylacetate;bromide Chemical compound [Br-].C1[N@@+](CC(=O)OCC)(C)CC[C@H]1OC(=O)[C@](O)(C=1C=CC=CC=1)C1CCCC1 FIAFMTCUJCWADZ-WVXMCOPUSA-M 0.000 claims abstract description 53
- 229950008610 sofpironium bromide Drugs 0.000 claims abstract description 53
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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
Disclosed is a pharmaceutical preparation to be applied once a day to both axillae and comprising sofpironium bromide as an active ingredient, the preparation being for treating primary axillary hyperhidrosis wherein the overall bilateral-axillary gravimetric sweat production measured according to the gravimetric method for five minutes before treatment is 400 mg or greater.
Description
本発明は、原発性腋窩多汗症の治療方法、及び、原発性腋窩多汗症を処置、治療、又は予防するためのソフピロニウム臭化物を含有する医薬製剤に関する。
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.
多汗症とは、温熱、精神的な負荷又はそれ以外の原因で手掌、足底に大量の発汗が起こり、日常生活での支障（例えば、書類やノートが汗で破れる、汗を気にして他人と手をつなげない、1日に何度も下着を取り替える必要がある、携帯電話が汗で濡れて壊れる等）をきたす状態であり、QOL を著しく低下させる（非特許文献１）。ヒトの汗腺にはエクリン汗腺、アポクリン汗腺が存在し、多汗症の原因となる汗はこのうちエクリン汗腺から分泌される（非特許文献２）。エクリン汗腺はコリン作動性神経により調節されており、アセチルコリンがエクリン汗腺を制御する神経のシナプス後膜に位置するM3型のムスカリン受容体を刺激することにより発汗を誘発すると考えられている（非特許文献３）。
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).
多汗症は、発症部位が全身的か体の一部かによって全身性多汗症と局所性多汗症に分類され、局所多汗症は手掌、足底、腋窩に生じることが多い。また、病因によって特に原因のない原発性と他の疾患（全身性では薬物性や循環器疾患等、局所性では末梢神経障害等）に合併して起きる続発性に分類される。以上より、原発性腋窩多汗症とは特定の原因によらずに腋窩に大量の発汗が起こり日常生活に支障をきたす状態であると定義できる。
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.
原発性多汗症の重症度や治療効果は、自覚症状を基にして以下の4段階：(1)発汗はまったく気にならず、日常生活に全く支障がない；(2)発汗は我慢できるが、日常生活に時々支障がある；(3)発汗はほとんど我慢できず、日常生活に頻繁に支障がある；(4)発汗は我慢できず、日常生活に常に支障がある、により分類したHyperhidrosis Disease Severity Scale（HDSS、Struttonら）に従って判定することができる。HDSSでは上記(1)～(4)の4スコアで判定を行うが、(3)及び(4)が重症の指標とされていることから、以下の本明細書においても、重症の原発性多汗症は、HDSSスコアの(3)及び(4)の病態を指す場合がある。他にヨード紙法や重量測定法などの発汗量測定も重症度や治療効果の判定に用いられる(非特許文献１)。
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).
2009年から2010年にかけて日本で実施された疫学調査（非特許文献４）（回答数：5807）によると日本の原発性腋窩多汗症の有病率は5.75%であり、平均発症年齢は19.5歳である。そのうち腋窩多汗症を含む原発性局所多汗症患者の医療機関への受診率は6.3%であり、全体の患者の47.8%が制汗作用のないデオドラント剤を使用していることから、適切な治療環境の整備や患者に対する啓発が必要な疾患である。
According to an epidemiological survey conducted in Japan from 2009 to 2010 (Non-Patent Document 4) (number of responses: 5807), 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.
原発性多汗症ガイドライン2015年改訂版（非特許文献1）によれば、原発性腋窩多汗症治療の第1選択は塩化アルミニウムの単純外用又は密封療法（Occlusive dressing technique, ODT）であり、これで効果がない場合の第2選択はA型ボツリヌス毒素（ボトックス（登録商標）注用50単位）の皮内投与である。その他の選択として、胸腔鏡下胸部交感神経遮断術（Endoscopic thoracic sympathectomy, ETS）等の手術療法や神経ブロック、レーザー療法、抗コリン剤の内服療法、精神（心理）療法が使用される場合もあるが推奨度は低い。
According to the 2015 revised edition of the Guidelines for Primary Hyperhidrosis (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. However, the recommendation level is low.
しかしながら、上記の既存治療には以下の問題点がある。
塩化アルミニウムの外用投与は、日本では公的保険の適応でなく、かつ、刺激性皮膚炎が発現する場合があり、これを発症した場合には投薬の休止やステロイド外用剤による治療を要することから長期的な使用が難しい。
A型ボツリヌス毒素の皮内投与は、複数ヵ所（10～15ヵ所）に1～2 cm間隔で皮内投与するため、痛みを伴う治療である。また、誤投与を防止するためボトックス（登録商標）を使用する医師は実技講習を受ける必要があり、臨床上簡便に用いることができない。 However, the above-mentioned existing treatment has the following problems.
External administration of aluminum chloride is not covered by public insurance in Japan, and irritant dermatitis may develop. If this occurs, medication should be discontinued or treatment with topical steroids is required. Difficult to use for a long time.
Intradermal administration of botulinum toxin type A is a painful treatment because it is administered intradermally to multiple sites (10 to 15 sites) at intervals of 1 to 2 cm. In addition, doctors who use Botox (registered trademark) need to take practical training to prevent erroneous administration, and it cannot be used clinically easily.
塩化アルミニウムの外用投与は、日本では公的保険の適応でなく、かつ、刺激性皮膚炎が発現する場合があり、これを発症した場合には投薬の休止やステロイド外用剤による治療を要することから長期的な使用が難しい。
A型ボツリヌス毒素の皮内投与は、複数ヵ所（10～15ヵ所）に1～2 cm間隔で皮内投与するため、痛みを伴う治療である。また、誤投与を防止するためボトックス（登録商標）を使用する医師は実技講習を受ける必要があり、臨床上簡便に用いることができない。 However, the above-mentioned existing treatment has the following problems.
External administration of aluminum chloride is not covered by public insurance in Japan, and irritant dermatitis may develop. If this occurs, medication should be discontinued or treatment with topical steroids is required. Difficult to use for a long time.
Intradermal administration of botulinum toxin type A is a painful treatment because it is administered intradermally to multiple sites (10 to 15 sites) at intervals of 1 to 2 cm. In addition, doctors who use Botox (registered trademark) need to take practical training to prevent erroneous administration, and it cannot be used clinically easily.
ETS等の手術療法は、不可逆的な治療であり、他の部位から異常発汗が起こる代償性発汗が起きる場合があるため、臨床上簡便に適用することができない。
抗コリン剤の内服療法は、抗コリン作用に起因する口渇、眠気、悪心等の全身性の副作用が発現する。国内で多汗症に対する保険適応を有するプロ・バンサイン（登録商標）錠15 mgのインタビューフォームによると、口渇（約30%）、便秘（約12%）、排尿障害（約9%）、眼の調節障害（約9%）の発生頻度が比較的高い。抗コリン剤の内服療法では、これらの副作用のために、十分な有効性を発揮できる量を使用できない場合がある。
以上のように、既存の治療方法には侵襲性及び全身性の副作用に問題があり、これを回避できる薬剤が求められている。 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. According to an interview form of 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.
As described above, existing treatment methods have problems with invasive and systemic side effects, and there is a need for a drug capable of avoiding these problems.
抗コリン剤の内服療法は、抗コリン作用に起因する口渇、眠気、悪心等の全身性の副作用が発現する。国内で多汗症に対する保険適応を有するプロ・バンサイン（登録商標）錠15 mgのインタビューフォームによると、口渇（約30%）、便秘（約12%）、排尿障害（約9%）、眼の調節障害（約9%）の発生頻度が比較的高い。抗コリン剤の内服療法では、これらの副作用のために、十分な有効性を発揮できる量を使用できない場合がある。
以上のように、既存の治療方法には侵襲性及び全身性の副作用に問題があり、これを回避できる薬剤が求められている。 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. According to an interview form of 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.
As described above, existing treatment methods have problems with invasive and systemic side effects, and there is a need for a drug capable of avoiding these problems.
ところで、アセチルコリンは、生体の主要な神経伝達物質の一つとして知られ、多様な薬理作用を有しており、汗腺の活性化による発汗作用もその一つである。したがって、抗コリン剤は、アセチルコリンの作用を阻害することで多汗症の治療に有用である。さらに、抗コリン剤を外用塗布することで、経口投与に伴う副作用を緩和しうる。加えて、既存治療法で発生する可能性のある副作用、即ち、塩化アルミニウム外用療法における刺激性皮膚炎の発症、あるいは、ボツリヌス毒素の投与時の注射時痛、及び、一過性の筋力低下などの副作用を回避することができる。
By the way, 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.
多汗症の治療に有用な外用塗布用の抗コリン剤としては、ソフトグリコピロレートが挙げられる（特許文献１）。ソフトグリコピロレートは、抗コリン剤であるグリコピロレートの誘導体であり、代表的なソフトグリコピロレートの一つとして、ソフピロニウム臭化物がある。
As an anticholinergic agent for external application useful for the treatment of hyperhidrosis, soft glycopyrrolate can be mentioned (Patent Document 1). Soft glycopyrrolate is a derivative of glycopyrrolate, which is an anticholinergic agent, and one of the typical soft glycopyrrolate is sofpironium bromide.
ソフピロニウム臭化物は、下記式（Ｉ）：
で表されるエステル化合物（以下、「BBI-4000」又は「化合物（I）」と言う場合がある。）であり、４級アンモニウムの臭化物塩である。これまで、ソフピロニウム臭化物の外用塗布製剤と、それを用いた多汗症治療方法が報告されている。
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.
特許文献１において、ソフトグリコピロレートが多汗症の処置に用いることができる旨が開示されている。
特許文献２において、腋窩多汗症の被験体において局所的に適用した場合のBBI-4000の処置効果について示唆される。
特許文献３及び４において、多汗症を有する対象において局所的に適用されたBBI-4000の安全性および汗の生成に対する効果が示される（BBI-4000-CL-101研究）。 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).
特許文献２において、腋窩多汗症の被験体において局所的に適用した場合のBBI-4000の処置効果について示唆される。
特許文献３及び４において、多汗症を有する対象において局所的に適用されたBBI-4000の安全性および汗の生成に対する効果が示される（BBI-4000-CL-101研究）。 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).
しかしながら、これまで、有効成分としてソフピロニウム臭化物を含有する外用塗布するための医薬製剤において、原発性腋窩多汗症の重症度に即した治療方法やその医薬については開示も示唆もない。
However, until now, there has been no disclosure or suggestion of a therapeutic method or a drug for external application containing sofpironium bromide as an active ingredient, which is suitable for the severity of primary axillary hyperhidrosis.
これまで、ソフピロニウム臭化物を含有する製剤において、原発性腋窩多汗症の重症度に即した多汗症の治療方法やその医薬については開示も示唆もされておらず、特に、多量の発汗を伴う重症の原発性腋窩多汗症の治療方法やその医薬については、全く知られていない。
そこで、本発明が解決しようとする課題の一つは、ソフピロニウム臭化物を有効成分として含み、外用塗布するための臨床で有効な医薬製剤を提供することである。
本発明が解決しようとする別の課題は、ソフピロニウム臭化物を有効成分として含み、外用塗布するための臨床で有効な医薬製剤を重症度に即して使用する方法を提供することである。 So far, no disclosure or suggestion has been made or suggested regarding a treatment method for hyperhidrosis or a drug thereof according to the severity of primary axillary hyperhidrosis in a preparation containing sofpironium bromide, and in particular, a large amount of sweating is involved. Nothing is known about the treatment or drug for severe primary axillary hyperhidrosis.
Therefore, 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.
そこで、本発明が解決しようとする課題の一つは、ソフピロニウム臭化物を有効成分として含み、外用塗布するための臨床で有効な医薬製剤を提供することである。
本発明が解決しようとする別の課題は、ソフピロニウム臭化物を有効成分として含み、外用塗布するための臨床で有効な医薬製剤を重症度に即して使用する方法を提供することである。 So far, no disclosure or suggestion has been made or suggested regarding a treatment method for hyperhidrosis or a drug thereof according to the severity of primary axillary hyperhidrosis in a preparation containing sofpironium bromide, and in particular, a large amount of sweating is involved. Nothing is known about the treatment or drug for severe primary axillary hyperhidrosis.
Therefore, 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.
本発明が解決しようとするさらに別の課題の一つは、治療前の5分間の両腋窩合計発汗重量が100 mg以上である原発性腋窩多汗症に有効な治療薬又は治療方法を提供することである。
本発明が解決しようとするさらに別の課題の一つは、治療前の5分間の両腋窩合計発汗重量が400 mg以上である重症の原発性腋窩多汗症に有効な治療薬又は治療方法を提供することである。
また、本発明が解決しようとするさらに別の課題の一つは、原発性腋窩多汗症に有効で長期投与可能な治療薬又は治療方法を提供することである。 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. To provide.
Moreover, 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.
本発明が解決しようとするさらに別の課題の一つは、治療前の5分間の両腋窩合計発汗重量が400 mg以上である重症の原発性腋窩多汗症に有効な治療薬又は治療方法を提供することである。
また、本発明が解決しようとするさらに別の課題の一つは、原発性腋窩多汗症に有効で長期投与可能な治療薬又は治療方法を提供することである。 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. To provide.
Moreover, 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.
本発明者らは、ソフピロニウム臭化物の医薬製剤の臨床における治療効果を検討する過程において、１日１回両腋窩に塗布することを特徴とするソフピロニウム臭化物の医薬製剤が、HDSSスコアが３又は４である重症の原発性腋窩多汗症、及び／又は、治療前の5分間の両腋窩合計発汗重量が100 mg以上である原発性腋窩多汗症に対して、臨床上有用であることを明らかにした。
特に、驚くべきことに、本発明者らは、前記医薬製剤が、治療前の5分間の両腋窩合計発汗重量が400 mg以上である重症の原発性腋窩多汗症に対して、臨床上極めて有用であることを明らかにした。 In the process of examining the clinical therapeutic effect of a pharmaceutical preparation of sofpironium bromide, 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.
In particular, surprisingly, 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.
特に、驚くべきことに、本発明者らは、前記医薬製剤が、治療前の5分間の両腋窩合計発汗重量が400 mg以上である重症の原発性腋窩多汗症に対して、臨床上極めて有用であることを明らかにした。 In the process of examining the clinical therapeutic effect of a pharmaceutical preparation of sofpironium bromide, 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.
In particular, surprisingly, 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.
さらに、本発明者らは、前記医薬製剤が、長期投与において、有効性及び安全性が担保されることを明らかにし、本発明を完成させた。
本発明は、原発性多汗症の処置、治療、又は予防をするための、ソフピロニウム臭化物の医薬製剤を含む。さらに、本発明は、ソフピロニウム臭化物の医薬製剤を用いた、原発性多汗症の処置、治療、又は予防をする方法を含む。 Furthermore, the present inventors have clarified that the efficacy and safety of the pharmaceutical preparation are guaranteed in long-term administration, and completed the present invention.
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.
本発明は、原発性多汗症の処置、治療、又は予防をするための、ソフピロニウム臭化物の医薬製剤を含む。さらに、本発明は、ソフピロニウム臭化物の医薬製剤を用いた、原発性多汗症の処置、治療、又は予防をする方法を含む。 Furthermore, the present inventors have clarified that the efficacy and safety of the pharmaceutical preparation are guaranteed in long-term administration, and completed the present invention.
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.
即ち、本発明は、以下の発明を包含する。
［０１］ ソフピロニウム臭化物を有効成分として含み、1日1回、両腋窩に塗布するための医薬製剤であって、治療前の5分間の重量測定法による両腋窩合計発汗重量が400 mg以上である原発性腋窩多汗症を治療するための製剤。 That is, the present invention includes the following inventions.
[01] 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. A preparation for treating primary axillary hyperhidrosis.
［０１］ ソフピロニウム臭化物を有効成分として含み、1日1回、両腋窩に塗布するための医薬製剤であって、治療前の5分間の重量測定法による両腋窩合計発汗重量が400 mg以上である原発性腋窩多汗症を治療するための製剤。 That is, the present invention includes the following inventions.
[01] 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. A preparation for treating primary axillary hyperhidrosis.
［０２］ ソフピロニウム臭化物の含有量が、全製剤量に対して、5w/w%から15w/w%である、前記[０１]に記載の製剤。
［０３］ ソフピロニウム臭化物の含有量が、全製剤量に対して、5w/w%である、前記[０１]又は前記[０２]に記載の製剤。 [02] The preparation according to the above [01], wherein the content of the sofpironium bromide is 5 w / w% to 15 w / w% with respect to the total amount of the preparation.
[03] The preparation according to the above [01] or the above [02], wherein the content of the sofpironium bromide is 5 w / w% with respect to the total amount of the preparation.
［０３］ ソフピロニウム臭化物の含有量が、全製剤量に対して、5w/w%である、前記[０１]又は前記[０２]に記載の製剤。 [02] The preparation according to the above [01], wherein the content of the sofpironium bromide is 5 w / w% to 15 w / w% with respect to the total amount of the preparation.
[03] The preparation according to the above [01] or the above [02], wherein the content of the sofpironium bromide is 5 w / w% with respect to the total amount of the preparation.
［０４］ 各腋窩へ投与される製剤の一回の投与あたりの平均量が、0.5 mLから1.0 mLであることを特徴とする、前記[０１]から前記[０３]のいずれか一つに記載の製剤。
［０５］ 投与される一回の投与あたりのソフロピロニウム臭化物の平均量が、腋窩の身体表面1cm2あたり、5.0 μgから2000 μgであることを特徴とする、前記[０１]から前記[０４]のいずれか一つに記載の製剤。 [04] Described in any one of the above [01] to the above [03], wherein the average amount of the preparation to be administered to each axilla per administration is 0.5 mL to 1.0 mL. Formulation of.
[05] The above-mentioned [01] to the above-mentioned [04], wherein the average amount of the sophropyrronium bromide per 1 cm 2 of the body surface of the axilla is 5.0 μg to 2000 μg per 1 cm 2 of the body surface of the axilla. The preparation according to any one.
［０５］ 投与される一回の投与あたりのソフロピロニウム臭化物の平均量が、腋窩の身体表面1cm2あたり、5.0 μgから2000 μgであることを特徴とする、前記[０１]から前記[０４]のいずれか一つに記載の製剤。 [04] Described in any one of the above [01] to the above [03], wherein the average amount of the preparation to be administered to each axilla per administration is 0.5 mL to 1.0 mL. Formulation of.
[05] The above-mentioned [01] to the above-mentioned [04], wherein the average amount of the sophropyrronium bromide per 1 cm 2 of the body surface of the axilla is 5.0 μg to 2000 μg per 1 cm 2 of the body surface of the axilla. The preparation according to any one.
［０６］ 治療前と比較して、治療期間中又は治療後にHDSSスコアを1以上低下させる制汗作用を有することを特徴とする、前記[０１]から前記[０５]のいずれか一つに記載の製剤。
［０７］ 前記原発性腋窩多汗症が、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症である、前記[０１]から前記[０６]のいずれか一つに記載の製剤。
［０８］ 前記原発性腋窩多汗症が、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症であり、治療終了時のHDSSスコアが1または2に改善することを特徴とする、前記[０１]から前記[０７]のいずれか一つに記載の製剤。
［０９］ 前記原発性腋窩多汗症が、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症であり、治療終了時のHDSSスコアが1または2に改善し、かつ、治療終了時の両腋窩合計発汗重量の治療前の両腋窩合計発汗重量との比が0.5以下に改善することを特徴とする、前記[０１]から前記[０８]のいずれか一つに記載の製剤。 [06] Described in any one of the above [01] to the above [05], which has an antiperspirant action that lowers the HDSS score by 1 or more during or after the treatment as compared with before the treatment. Formulation.
[07] The above-mentioned [01] to the above-mentioned [06], wherein the primary axillary hyperhidrosis is a severe primary axillary hyperhidrosis having an HDSS score of 3 or 4 before treatment. pharmaceutical formulation.
[08] The primary axillary hyperhidrosis is a 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. The preparation according to any one of the above [01] to the above [07].
[09] 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. The preparation according to any one of the above [01] to the above [08], wherein the ratio of the total sweating weight of both axillae at the end to the total sweating weight of both axillae before treatment is improved to 0.5 or less. ..
［０７］ 前記原発性腋窩多汗症が、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症である、前記[０１]から前記[０６]のいずれか一つに記載の製剤。
［０８］ 前記原発性腋窩多汗症が、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症であり、治療終了時のHDSSスコアが1または2に改善することを特徴とする、前記[０１]から前記[０７]のいずれか一つに記載の製剤。
［０９］ 前記原発性腋窩多汗症が、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症であり、治療終了時のHDSSスコアが1または2に改善し、かつ、治療終了時の両腋窩合計発汗重量の治療前の両腋窩合計発汗重量との比が0.5以下に改善することを特徴とする、前記[０１]から前記[０８]のいずれか一つに記載の製剤。 [06] Described in any one of the above [01] to the above [05], which has an antiperspirant action that lowers the HDSS score by 1 or more during or after the treatment as compared with before the treatment. Formulation.
[07] The above-mentioned [01] to the above-mentioned [06], wherein the primary axillary hyperhidrosis is a severe primary axillary hyperhidrosis having an HDSS score of 3 or 4 before treatment. pharmaceutical formulation.
[08] The primary axillary hyperhidrosis is a 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. The preparation according to any one of the above [01] to the above [07].
[09] 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. The preparation according to any one of the above [01] to the above [08], wherein the ratio of the total sweating weight of both axillae at the end to the total sweating weight of both axillae before treatment is improved to 0.5 or less. ..
［１０］ 治療期間中に交感神経遮断術を実施することなく原発性腋窩多汗症を治療することができることを特徴とする、前記[０１]から前記[０９]のいずれか一つに記載の製剤。
［１１］ ソフピロニウム臭化物の医薬製剤が少なくとも6週間の治療期間にわたって１日１回投与されることを特徴とする、前記[０１]から前記[１０]のいずれか一つに記載の製剤。
［１２］ ソフピロニウム臭化物の医薬製剤が6週間から52週間の治療期間にわたって１日１回投与されることを特徴とする、前記[０１]から前記[１０]のいずれか一つに記載の製剤。 [10] The description according to any one of the above [01] to the above [09], wherein the primary axillary hyperhidrosis can be treated without performing sympathetic nerve blockade during the treatment period. pharmaceutical formulation.
[11] The preparation according to any one of the above [01] to the above [10], wherein the pharmaceutical preparation of sofpironium bromide is administered once a day for a treatment period of at least 6 weeks.
[12] The preparation according to any one of the above [01] to the above [10], wherein the pharmaceutical preparation of sofpironium bromide is administered once a day for a treatment period of 6 to 52 weeks.
［１１］ ソフピロニウム臭化物の医薬製剤が少なくとも6週間の治療期間にわたって１日１回投与されることを特徴とする、前記[０１]から前記[１０]のいずれか一つに記載の製剤。
［１２］ ソフピロニウム臭化物の医薬製剤が6週間から52週間の治療期間にわたって１日１回投与されることを特徴とする、前記[０１]から前記[１０]のいずれか一つに記載の製剤。 [10] The description according to any one of the above [01] to the above [09], wherein the primary axillary hyperhidrosis can be treated without performing sympathetic nerve blockade during the treatment period. pharmaceutical formulation.
[11] The preparation according to any one of the above [01] to the above [10], wherein the pharmaceutical preparation of sofpironium bromide is administered once a day for a treatment period of at least 6 weeks.
[12] The preparation according to any one of the above [01] to the above [10], wherein the pharmaceutical preparation of sofpironium bromide is administered once a day for a treatment period of 6 to 52 weeks.
［１３］ 全製剤量に対し5w/w％のソフピロニウム臭化物を有効成分として含み、両腋窩に、6週間を超えて52週間の治療期間にわたって１日１回投与されることを特徴とする、塗布するための医薬製剤であって、治療前の5分間の重量測定法による両腋窩合計発汗重量が100 mg以上である原発性腋窩多汗症を治療するための製剤。
[13] An application containing 5 w / w% of sofpironium bromide as an active ingredient with respect to the total amount of the pharmaceutical product, which is administered to both axillas once a day for a treatment period of more than 6 weeks and 52 weeks. A pharmaceutical preparation for treating primary axillary hyperhidrosis in which the total axillary sweating weight of both axillae is 100 mg or more by a 5-minute weight measurement method before treatment.
［１４］ pHが5.2以下である、前記[０１]から前記[１３]のいずれか一つに記載の製剤。
［１５］ 全製剤量に対して0.015w/w%から0.1w/w%未満の無水クエン酸を含む、前記[０１]から前記[１４]のいずれか一つに記載の製剤。
［１６］ ソフピロニウム臭化物の医薬製剤が、全製剤量に対して1.25w/w%のヒドロキシプロピルセルロースと、2.5w/w%のミリスチン酸イソプロピルと、0.05w/w%の無水クエン酸と、10w/w%のへキシレングリコールと、無水エタノールが残分として構成される、前記[０１]から前記[１４]のいずれか一つに記載の製剤。 [14] The preparation according to any one of the above [01] to the above [13], which has a pH of 5.2 or less.
[15] The preparation according to any one of the above [01] to the above [14], which comprises 0.015 w / w% to less than 0.1 w / w% anhydrous citric acid with respect to the total amount of the preparation.
[16] The pharmaceutical formulations of sofpironium bromide consist of 1.25 w / w% hydroxypropyl cellulose, 2.5 w / w% isopropyl myristate, 0.05 w / w% anhydrous citric acid, and 10 w. The preparation according to any one of the above [01] to the above [14], which comprises / w% hexylene glycol and absolute ethanol as a residue.
［１５］ 全製剤量に対して0.015w/w%から0.1w/w%未満の無水クエン酸を含む、前記[０１]から前記[１４]のいずれか一つに記載の製剤。
［１６］ ソフピロニウム臭化物の医薬製剤が、全製剤量に対して1.25w/w%のヒドロキシプロピルセルロースと、2.5w/w%のミリスチン酸イソプロピルと、0.05w/w%の無水クエン酸と、10w/w%のへキシレングリコールと、無水エタノールが残分として構成される、前記[０１]から前記[１４]のいずれか一つに記載の製剤。 [14] The preparation according to any one of the above [01] to the above [13], which has a pH of 5.2 or less.
[15] The preparation according to any one of the above [01] to the above [14], which comprises 0.015 w / w% to less than 0.1 w / w% anhydrous citric acid with respect to the total amount of the preparation.
[16] The pharmaceutical formulations of sofpironium bromide consist of 1.25 w / w% hydroxypropyl cellulose, 2.5 w / w% isopropyl myristate, 0.05 w / w% anhydrous citric acid, and 10 w. The preparation according to any one of the above [01] to the above [14], which comprises / w% hexylene glycol and absolute ethanol as a residue.
［１７］ 治療前のHDSSスコアが3又は4として定義される重症の原発性腋窩多汗症を処置、又は治療する方法であって、
a) ソフピロニウム臭化物を有効成分として含む医薬製剤を、1日1回、両腋窩に塗布することと、
b）治療終了時のHDSSスコアが1または2に改善し、かつ、治療終了時の両腋窩合計発汗重量の治療前の両腋窩合計発汗重量との比が0.5以下に改善することを特徴とする、方法。
［１８］ 治療前の5分間の重量測定法による両腋窩合計発汗重量が400 mg以上である原発性腋窩多汗症を治療するための、前記［１７］に記載の方法。
［１９］ ソフピロニウム臭化物の医薬製剤が少なくとも6週間の治療期間にわたって１日１回投与されることを特徴とする、前記[１７]または前記[１８]に記載の方法。 [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) ソフピロニウム臭化物を有効成分として含む医薬製剤を、1日1回、両腋窩に塗布することと、
b）治療終了時のHDSSスコアが1または2に改善し、かつ、治療終了時の両腋窩合計発汗重量の治療前の両腋窩合計発汗重量との比が0.5以下に改善することを特徴とする、方法。
［１８］ 治療前の5分間の重量測定法による両腋窩合計発汗重量が400 mg以上である原発性腋窩多汗症を治療するための、前記［１７］に記載の方法。
［１９］ ソフピロニウム臭化物の医薬製剤が少なくとも6週間の治療期間にわたって１日１回投与されることを特徴とする、前記[１７]または前記[１８]に記載の方法。 [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.
本発明によれば、ソフピロニウム臭化物の医薬製剤を、治療前の5分間の両腋窩合計発汗重量が100 mg以上である原発性腋窩多汗症の治療に用いることができ、特に、治療前の5分間の両腋窩合計発汗重量が400 mg以上である重症の原発性腋窩多汗症の治療に用いることができる。
According to the present invention, 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.
以下、本発明について、詳細に説明する。
本発明の製剤は、有効成分としてソフピロニウム臭化物を含有する局所投与するための外用の医薬製剤である。
本発明において、処置、治療、及び／又は予防されるべき疾患は、多汗症であり、好ましくは、原発性多汗症であり、より好ましくは、原発性局所多汗症であり、より一層好ましくは、原発性腋窩多汗症である。 Hereinafter, the present invention will be described in detail.
The preparation of the present invention is an external pharmaceutical preparation for topical administration containing sofpironium bromide as an active ingredient.
In the present invention, 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.
本発明の製剤は、有効成分としてソフピロニウム臭化物を含有する局所投与するための外用の医薬製剤である。
本発明において、処置、治療、及び／又は予防されるべき疾患は、多汗症であり、好ましくは、原発性多汗症であり、より好ましくは、原発性局所多汗症であり、より一層好ましくは、原発性腋窩多汗症である。 Hereinafter, the present invention will be described in detail.
The preparation of the present invention is an external pharmaceutical preparation for topical administration containing sofpironium bromide as an active ingredient.
In the present invention, 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.
本発明の製剤は、1日1回投与され、好ましくは、1日1回適量を局所塗布される。
一般に原発性の局所性多汗症では、頭部・顔面、手掌、足底、腋窩などに左右対称に過剰な発汗が生じることから、本発明の製剤は、好ましくは両腋窩、両手掌に塗布するための外用製剤である。しかし、片側腋窩又は片側手掌などに過剰な発汗が生じる場合には、本発明の製剤を当該片側腋窩又は片側手掌などに適用することもできる。 The pharmaceutical product of the present invention is administered once a day, and preferably an appropriate amount is locally applied once a day.
Generally, in primary local hyperhidrosis, excessive sweating occurs symmetrically on the head / face, palm, sole, axilla, etc. Therefore, the preparation of the present invention is preferably applied to both axilla and palm. It is an external preparation for use. However, when excessive sweating occurs in the one-sided axilla or one-sided palm, the preparation of the present invention can also be applied to the one-sided axilla or one-sided palm.
一般に原発性の局所性多汗症では、頭部・顔面、手掌、足底、腋窩などに左右対称に過剰な発汗が生じることから、本発明の製剤は、好ましくは両腋窩、両手掌に塗布するための外用製剤である。しかし、片側腋窩又は片側手掌などに過剰な発汗が生じる場合には、本発明の製剤を当該片側腋窩又は片側手掌などに適用することもできる。 The pharmaceutical product of the present invention is administered once a day, and preferably an appropriate amount is locally applied once a day.
Generally, in primary local hyperhidrosis, excessive sweating occurs symmetrically on the head / face, palm, sole, axilla, etc. Therefore, the preparation of the present invention is preferably applied to both axilla and palm. It is an external preparation for use. However, when excessive sweating occurs in the one-sided axilla or one-sided palm, the preparation of the present invention can also be applied to the one-sided axilla or one-sided palm.
本発明の一実施態様において、本発明の製剤は、6～48時間の間隔、8～36時間の間隔、12～36時間の間隔、20～28時間の間隔、又は22～26時間の間隔で投与される。
本発明の一実施態様において、本発明の製剤は、就寝前に投与される。
本発明の別の実施態様において、本発明の製剤は、就寝前に1日1回投与される。
本発明の別の実施態様において、本発明の製剤は、就寝前に、6～48時間の間隔、8～36時間の間隔、12～36時間の間隔、20～28時間の間隔、又は22～26時間の間隔で投与される。 In one embodiment of the invention, 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.
In one embodiment of the invention, the pharmaceutical product of the present invention is administered before bedtime.
In another embodiment of the invention, the pharmaceutical product of the present invention is administered once daily before bedtime.
In another embodiment of the invention, 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.
本発明の一実施態様において、本発明の製剤は、就寝前に投与される。
本発明の別の実施態様において、本発明の製剤は、就寝前に1日1回投与される。
本発明の別の実施態様において、本発明の製剤は、就寝前に、6～48時間の間隔、8～36時間の間隔、12～36時間の間隔、20～28時間の間隔、又は22～26時間の間隔で投与される。 In one embodiment of the invention, 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.
In one embodiment of the invention, the pharmaceutical product of the present invention is administered before bedtime.
In another embodiment of the invention, the pharmaceutical product of the present invention is administered once daily before bedtime.
In another embodiment of the invention, 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.
本明細書中、治療前に測定した5分間の両腋窩合計発汗重量が400 mg以上である原発性腋窩多汗症を「重症」と記載する場合がある。ただし、これは、自覚症状により判断されるHDSSに基づく重症度と必ずしも一致するものではない。
In the present specification, primary axillary hyperhidrosis in which the total sweating weight of both axillae for 5 minutes measured before treatment is 400 mg or more may be described as "severe". However, this does not necessarily correspond to the severity based on HDSS, which is judged by subjective symptoms.
本明細書中、特に注記がなければ、発汗重量は、重量測定法により測定される。重量測定法としては、一般的には、ろ紙またはガーゼを一定時間腋窩に接着させて、その発汗重量を計測する方法を採用することができる。典型的な重量測定法は、あらかじめ重量を測定したろ紙を被験者の両腋窩に5分間装着させ、その重量を測定し、風袋重量との差分をとる工程を含むが、必要に応じてそれらのうちの１又は２以上の工程を省略し、あるいは必要に応じて１又は２以上の追加工程を付加することもできる。
本明細書中、「発汗重量」とは、測定値を指す場合、特に注記がなければ、発汗重量測定法による5 分間の測定値である。 Unless otherwise noted in the present specification, sweating weight is measured by a weight measuring method. As 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.
In the present specification, “sweat weight” refers to a measured value, which is a measured value for 5 minutes by the sweating weight measuring method unless otherwise specified.
本明細書中、「発汗重量」とは、測定値を指す場合、特に注記がなければ、発汗重量測定法による5 分間の測定値である。 Unless otherwise noted in the present specification, sweating weight is measured by a weight measuring method. As 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.
In the present specification, “sweat weight” refers to a measured value, which is a measured value for 5 minutes by the sweating weight measuring method unless otherwise specified.
本発明の製剤を用いた治療期間は、本発明の効果が発揮されれば特に限定されない。
本発明の製剤は、長期投与においても、有効性及び安全性が担保される点に特徴を有する。
例えば、本発明の一実施態様において、本発明の製剤を用いた治療期間は、2週間、4週間、6週間、12週間、24週間、36週間、48週間、52週間、2年、又は3年以上である。
本発明の別の実施態様において、本発明の製剤の投与期間は、少なくとも6週間、少なくとも12週間、少なくとも24週間、少なくとも36週間、少なくとも48週間、又は少なくとも52週間である。
本発明の別の実施態様において、本発明の製剤を用いた治療期間は、6週間から24週間、6週間から36週間の範囲、6週間から48週間、又は6週間から52週間である。
本発明の別の実施態様において、本発明の製剤を用いた治療期間は、6週間を超えた期間、6週間を超えて24週間までの期間、6週間を超えて36週間までの期間、6週間を超えて48週間までの期間、又は6週間を超えて52週間までの期間である。 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.
For example, in one embodiment of the present invention, 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.
In another embodiment of the invention, 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.
In another embodiment of the invention, 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.
In another embodiment of the present invention, 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.
本発明の製剤は、長期投与においても、有効性及び安全性が担保される点に特徴を有する。
例えば、本発明の一実施態様において、本発明の製剤を用いた治療期間は、2週間、4週間、6週間、12週間、24週間、36週間、48週間、52週間、2年、又は3年以上である。
本発明の別の実施態様において、本発明の製剤の投与期間は、少なくとも6週間、少なくとも12週間、少なくとも24週間、少なくとも36週間、少なくとも48週間、又は少なくとも52週間である。
本発明の別の実施態様において、本発明の製剤を用いた治療期間は、6週間から24週間、6週間から36週間の範囲、6週間から48週間、又は6週間から52週間である。
本発明の別の実施態様において、本発明の製剤を用いた治療期間は、6週間を超えた期間、6週間を超えて24週間までの期間、6週間を超えて36週間までの期間、6週間を超えて48週間までの期間、又は6週間を超えて52週間までの期間である。 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.
For example, in one embodiment of the present invention, 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.
In another embodiment of the invention, 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.
In another embodiment of the invention, 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.
In another embodiment of the present invention, 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.
本発明の製剤中に含まれるソフピロニウム臭化物の含有量としては、特に限定されないが、1w/w%から30w/w%が好ましく、より好ましくは1w/w%から20w/w%であり、さらに好ましくは5w/w%から15w/w%である。
本発明の一実施態様において、好ましいソフピロニウム臭化物の含有量は、全製剤量に対して、5w/w%、10w/w%、又は15w/w%であり、特に好ましくは5w/w%である。
なお、本明細書中、「AからB」あるいは「A～B」などと、範囲を記載する場合は、特に注記がなければ、その末端の数値も含む。 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%.
In one embodiment of the present invention, 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. ..
In the present specification, when 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.
本発明の一実施態様において、好ましいソフピロニウム臭化物の含有量は、全製剤量に対して、5w/w%、10w/w%、又は15w/w%であり、特に好ましくは5w/w%である。
なお、本明細書中、「AからB」あるいは「A～B」などと、範囲を記載する場合は、特に注記がなければ、その末端の数値も含む。 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%.
In one embodiment of the present invention, 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. ..
In the present specification, when 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.
本発明において、ソフピロニウム臭化物の医薬製剤の各腋窩への一回投与あたりの製剤の平均量は、好ましくは0.1 mLから2.0 mLであり、より好ましくは0.5 mLから1.0 mLであり、さらに好ましくは0.6 mLから0.7 mLである。
In the present invention, 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.
本発明において、腋窩の身体表面1cm2あたりに塗布される1回投与の有効成分（ソフピロニウム臭化物）の平均量は、好ましくは1.0 μgから5000 μgである、より好ましくは5.0 μgから2000 μgであり、さらに好ましくは10 μgから1000 μgであり、より一層好ましくは100 μgから1000 μgである。
In the present invention, 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 μg to 5000 μg, more preferably 5.0 μg to 2000 μg. , More preferably 10 μg to 1000 μg, and even more preferably 100 μg to 1000 μg.
本発明の一実施態様において、本発明の製剤の一回使用量を、塗布具等に受けとり、塗布具等を腋窩に押し当てることで、腋窩に一回の投与量の前記製剤を塗布することができる。
上記のように塗布具等を用いることで、予め定めた量を適切に腋窩に投与すことができ、かつ、操作する手などに製剤が付着しにくいため、コンタミネーション等が生じず使用者にとって有益である。 In one embodiment of the present invention, 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. Can be done.
By using 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.
上記のように塗布具等を用いることで、予め定めた量を適切に腋窩に投与すことができ、かつ、操作する手などに製剤が付着しにくいため、コンタミネーション等が生じず使用者にとって有益である。 In one embodiment of the present invention, 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. Can be done.
By using 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.
本発明の一実施態様において、本発明の製剤と共に用いられる塗布具は、前記製剤を保管する容器本体と分離可能に接続される。
本発明の別の実施態様においては、本発明の製剤と共に用いられる塗布具は、前記製剤を保管する容器本体と分離不可能に接続される。この場合、例えば、塗布具の適用面中央部に、容器本体から前記製剤を吐出する吐出孔が設けられていてもよい。 In one embodiment of the present invention, the coating tool used with the formulation of the present invention is separably connected to the container body for storing the formulation.
In another embodiment of the invention, the coating tool used with the formulation of the invention is inseparably connected to the container body in which the formulation is stored. In this case, for example, 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.
本発明の別の実施態様においては、本発明の製剤と共に用いられる塗布具は、前記製剤を保管する容器本体と分離不可能に接続される。この場合、例えば、塗布具の適用面中央部に、容器本体から前記製剤を吐出する吐出孔が設けられていてもよい。 In one embodiment of the present invention, the coating tool used with the formulation of the present invention is separably connected to the container body for storing the formulation.
In another embodiment of the invention, the coating tool used with the formulation of the invention is inseparably connected to the container body in which the formulation is stored. In this case, for example, 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.
本発明の一実施態様において、本発明の製剤は、中程度の粘度を有するゲル製剤又は外用液剤である。
ここで、中程度の粘度とは、100 mPa・s～2000 mPa・s（25℃）の粘度を指し、狭義には、100 mPa・s～1100 mPa・s（25℃）の粘度を指す。
本発明の別の実施態様において、本発明の製剤の粘度は、100 mPa・s～900 mPa・s（25℃）が好ましく、250 mPa・s～850 mPa・s（25℃）がより好ましい。
本発明の製剤は、長期投与可能であることから、長期的に粘度が保持されることが好ましい。例えば、0.015w/w%から0.1w/w%未満、0.015w/w%から0.075w/w%、又は0.05w/w%の無水クエン酸を含有するソフピロニウム臭化物製剤は、長期的に粘度が保持される。 In one embodiment of the present invention, the preparation of the present invention is a gel preparation or an external liquid preparation having a medium viscosity.
Here, 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).
In another embodiment of the present invention, 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. For example, 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.
ここで、中程度の粘度とは、100 mPa・s～2000 mPa・s（25℃）の粘度を指し、狭義には、100 mPa・s～1100 mPa・s（25℃）の粘度を指す。
本発明の別の実施態様において、本発明の製剤の粘度は、100 mPa・s～900 mPa・s（25℃）が好ましく、250 mPa・s～850 mPa・s（25℃）がより好ましい。
本発明の製剤は、長期投与可能であることから、長期的に粘度が保持されることが好ましい。例えば、0.015w/w%から0.1w/w%未満、0.015w/w%から0.075w/w%、又は0.05w/w%の無水クエン酸を含有するソフピロニウム臭化物製剤は、長期的に粘度が保持される。 In one embodiment of the present invention, the preparation of the present invention is a gel preparation or an external liquid preparation having a medium viscosity.
Here, 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).
In another embodiment of the present invention, 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. For example, 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.
本発明は、ソフピロニウム臭化物を含む製剤をヒトへ投与する方法であって、原発性多汗症、腋窩多汗症、特に原発性腋窩多汗症を処置、治療、又は予防する新たな方法を含む。
本発明は、1w/w%から15w/w%のソフピロニウム臭化物、さらに好ましくは5w/w%のソフピロニウム臭化物を含む薬学的に許容される製剤を、少なくとも6週間の治療期間にわたり、1日1回、両腋窩に塗布する方法を含む。 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.
本発明は、1w/w%から15w/w%のソフピロニウム臭化物、さらに好ましくは5w/w%のソフピロニウム臭化物を含む薬学的に許容される製剤を、少なくとも6週間の治療期間にわたり、1日1回、両腋窩に塗布する方法を含む。 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.
本明細書中、「HDSSスコアを1以上低下させる」とは、ある一定の治療期間の前後で、HDSSスコアが1以上低下することを指し、例えば、治療前にHDSSスコアが3だった被験者のHDSSスコアが、治療期間中又は治療後に2や1になることを指す。また、例えば、治療前にHDSSスコアが4だった被験者のHDSSスコアが、治療期間中又は治療後に3～1のいずれかの値になることを指す。
In the present specification, "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.
本発明の一実施態様において、本発明の製剤は、治療前と比較して、治療期間中又は治療後にHDSSスコアを少なくとも1つ低下させる制汗作用を有することを特徴とする。
本発明の一実施態様において、本発明の製剤は、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症の治療剤であって、治療前と比較して、治療期間中又は治療後にHDSSスコアを1以上低下させる制汗作用を有することを特徴とする。
本発明の一実施態様において、本発明の製剤は、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症の治療剤であって、治療期間中又は治療後に、HDSSスコアが1または2に改善することを特徴とする。
本発明の一実施態様において、本発明の製剤は、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症の治療剤であって、治療期間中又は治療後にHDSSスコアが1または2に改善し、かつ、治療終了時の両腋窩合計発汗重量の治療前の両腋窩合計発汗重量との比が0.5以下に改善することを特徴とする。 In one embodiment of the present invention, 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.
In one embodiment of the invention, 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.
In one embodiment of the invention, 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.
In one embodiment of the invention, 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.
本発明の一実施態様において、本発明の製剤は、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症の治療剤であって、治療前と比較して、治療期間中又は治療後にHDSSスコアを1以上低下させる制汗作用を有することを特徴とする。
本発明の一実施態様において、本発明の製剤は、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症の治療剤であって、治療期間中又は治療後に、HDSSスコアが1または2に改善することを特徴とする。
本発明の一実施態様において、本発明の製剤は、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症の治療剤であって、治療期間中又は治療後にHDSSスコアが1または2に改善し、かつ、治療終了時の両腋窩合計発汗重量の治療前の両腋窩合計発汗重量との比が0.5以下に改善することを特徴とする。 In one embodiment of the present invention, 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.
In one embodiment of the invention, 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.
In one embodiment of the invention, 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.
In one embodiment of the invention, 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.
本発明の一実施態様において、本発明の製剤は、治療前の両腋窩合計発汗重量が100 mg/5 min以上である原発性腋窩多汗症において、治療前と比較して、治療期間中又は治療後にHDSSスコアを1以上低下させる制汗作用を有することを特徴とする。
In one embodiment of the present invention, 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.
本発明の別の実施態様において、本発明の製剤は、治療前の両腋窩合計発汗重量が100 mg/5 min以上である原発性腋窩多汗症において、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症の治療剤であって、治療期間中又は治療後に、治療前と比較して、HDSSスコアを1以上低下させる制汗作用を有することを特徴とする。
In another embodiment of the invention, 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.
本発明の別の実施態様において、本発明の製剤は、治療前の両腋窩合計発汗重量が100 mg/5 min以上である原発性腋窩多汗症において、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症の治療剤であって、治療期間中又は治療後に、HDSSスコアが1または2に改善することを特徴とする。
In another embodiment of the invention, 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.
本発明の別の実施態様において、本発明の製剤は、治療前の両腋窩合計発汗重量が100 mg/5 min以上である原発性腋窩多汗症において、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症の治療剤であって、治療期間中又は治療後に、HDSSスコアが1または2に改善し、かつ、治療終了時の両腋窩合計発汗重量の治療前の両腋窩合計発汗重量との比が0.5以下に改善することを特徴とする。
In another embodiment of the invention, 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. A therapeutic agent for severe primary axillary hyperhidrosis, with an HDSS score of 1 or 2 during or after treatment, and a total sweating weight of both axillae at the end of treatment. It is characterized in that the ratio to the sweating weight is improved to 0.5 or less.
本発明の一実施態様において、本発明の製剤は、治療前の両腋窩合計発汗重量が400 mg/5 min以上である原発性腋窩多汗症において、治療前と比較して、治療期間中又は治療後にHDSSスコアを1以上低下させる制汗作用を有することを特徴とする。
本発明の別の実施態様において、本発明の製剤は、治療前の両腋窩合計発汗重量が400 mg/5 min以上である原発性腋窩多汗症において、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症の治療剤であって、治療期間中又は治療後に、治療前と比較して、HDSSスコアを1以上低下させる制汗作用を有することを特徴とする。 In one embodiment of the invention, 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.
In another embodiment of the invention, 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.
本発明の別の実施態様において、本発明の製剤は、治療前の両腋窩合計発汗重量が400 mg/5 min以上である原発性腋窩多汗症において、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症の治療剤であって、治療期間中又は治療後に、治療前と比較して、HDSSスコアを1以上低下させる制汗作用を有することを特徴とする。 In one embodiment of the invention, 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.
In another embodiment of the invention, 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.
本発明の別の実施態様において、本発明の製剤は、治療前の両腋窩合計発汗重量が400 mg/5 min以上である原発性腋窩多汗症において、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症の治療剤であって、治療期間中又は治療後に、HDSSスコアが1または2に改善することを特徴とする。
本発明の別の実施態様において、本発明の製剤は、治療前の両腋窩合計発汗重量が400 mg/5 min以上である原発性腋窩多汗症において、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症の治療剤であって、治療期間中又は治療後に、HDSSスコアが1または2、かつ、治療終了時の両腋窩合計発汗重量の治療前の両腋窩合計発汗重量との比が0.5以下に改善することを特徴とする。 In another embodiment of the invention, 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.
In another embodiment of the invention, 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. A therapeutic agent for severe primary axillary hyperhidrosis with an HDSS score of 1 or 2 during or after treatment and a total axillary sweating weight at the end of treatment with the total axillary sweating weight before treatment. It is characterized in that the ratio of is improved to 0.5 or less.
本発明の別の実施態様において、本発明の製剤は、治療前の両腋窩合計発汗重量が400 mg/5 min以上である原発性腋窩多汗症において、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症の治療剤であって、治療期間中又は治療後に、HDSSスコアが1または2、かつ、治療終了時の両腋窩合計発汗重量の治療前の両腋窩合計発汗重量との比が0.5以下に改善することを特徴とする。 In another embodiment of the invention, 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.
In another embodiment of the invention, 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. A therapeutic agent for severe primary axillary hyperhidrosis with an HDSS score of 1 or 2 during or after treatment and a total axillary sweating weight at the end of treatment with the total axillary sweating weight before treatment. It is characterized in that the ratio of is improved to 0.5 or less.
本発明の製剤は、本発明の製剤を投与する前に治療部位の汗、水分、及び汚れを拭きとる工程を必要とする場合がある。
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.
以下、各試験例に沿って、本発明にかかる製剤を実施例としてより詳細に説明する。ただし、本実施例に本発明を限定する意図ではない。
Hereinafter, the pharmaceutical product according to the present invention will be described in more detail with reference to each test example as an example. However, it is not intended to limit the present invention to the present embodiment.
［試験例1］
原発性腋窩多汗症患者を対象としたBBI-4000 の検証的試験 [Test Example 1]
A confirmatory study of BBI-4000 in patients with primary axillary hyperhidrosis
原発性腋窩多汗症患者を対象としたBBI-4000 の検証的試験 [Test Example 1]
A confirmatory study of BBI-4000 in patients with primary axillary hyperhidrosis
原発性腋窩多汗症患者を対象とした無作為化二重盲検並行群間比較により、ソフピロニウム臭化物含有外用医薬製剤（ソフピロニウム臭化物 5w/w%、ヒドロキシプロピルセルロース1.25w/w%、ミリスチン酸イソプロピル 2.5w/w%、無水クエン酸0.05w/w%、へキシレングリコール 10w/w%、残分が無水エタノールで構成される。）を1日1回就寝前に6週間、腋窩に塗布した際の有効性のプラセボ製剤（ソフピロニウム臭化物0w/w%）に対する優越性を検証した。主要評価項目は、治療終了時のHDSSスコアが1 又は2であり、治療終了時の両腋窩合計発汗重量のベースライン（治療前に測定した発汗重量）との比が0.5以下の被験者の割合とした。
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). When 2.5w / w%, 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 (sofpyronium bromide 0w / w%) 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 end of treatment to the baseline (sweat weight measured prior to treatment) of 0.5 or less. bottom.
本試験中、「治療前」とは、ソフピロニウム臭化物の医薬製剤の投与による治療が行われるよりも前の時点を指す。
本試験中、「治療終了時」とは、治療終了の基準となる来院時期を指す。治療終了時は、所定の投与期間後の3つの来院日からなり、治療終了時のHDSSスコア及び発汗重量は、特に注記がなければ、その中央値を指す。
本試験中、「治療期間中」とは、治療開始時と治療終了時の間の期間を指す。 In this study, "before treatment" refers to a time point prior to treatment by administration of a pharmaceutical preparation of sofpironium bromide.
During this study, "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.
During this study, "during treatment" refers to the period between the start of treatment and the end of treatment.
本試験中、「治療終了時」とは、治療終了の基準となる来院時期を指す。治療終了時は、所定の投与期間後の3つの来院日からなり、治療終了時のHDSSスコア及び発汗重量は、特に注記がなければ、その中央値を指す。
本試験中、「治療期間中」とは、治療開始時と治療終了時の間の期間を指す。 In this study, "before treatment" refers to a time point prior to treatment by administration of a pharmaceutical preparation of sofpironium bromide.
During this study, "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.
During this study, "during treatment" refers to the period between the start of treatment and the end of treatment.
本試験における「ベースライン」とは、投与前における基準となる症状の程度に関する各測定値をいう。ベースラインは投与前の指定された一定期間に測定される。
本試験例におけるベースラインのHDSSスコア及び発汗重量は、ベースライン1、ベースライン2、及びベースライン3と定義される9日以内での3回の来院日における各測定値の中央値を指す。
ソフピロニウム臭化物の医薬製剤の投与日数は、ベースライン3を1日目とした日数であり、「投与期間」や「投与週数」等の表現もこの基準に準ずる。ベースライン3が、ソフピロニウム臭化物の医薬製剤の投与を開始する日である。
本試験のタイムコースを図1に示す。 The "baseline" in this study 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.
本試験例におけるベースラインのHDSSスコア及び発汗重量は、ベースライン1、ベースライン2、及びベースライン3と定義される9日以内での3回の来院日における各測定値の中央値を指す。
ソフピロニウム臭化物の医薬製剤の投与日数は、ベースライン3を1日目とした日数であり、「投与期間」や「投与週数」等の表現もこの基準に準ずる。ベースライン3が、ソフピロニウム臭化物の医薬製剤の投与を開始する日である。
本試験のタイムコースを図1に示す。 The "baseline" in this study 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.
＜有効性に関する解析＞
(1) 有効性の主要解析
治療終了時のHDSSスコアが1又は2であり、治療終了時の両腋窩合計発汗重量のベースラインとの比が0.5 以下の被験者の割合の解析はカイ2乗検定によって行った。 <Analysis of effectiveness>
(1) Primary efficacy analysis Chi-square test is used to analyze the proportion of subjects with an HDSS score of 1 or 2 at the end of treatment and a ratio of total axillary sweating weight to baseline of 0.5 or less at the end of treatment. Went by.
(1) 有効性の主要解析
治療終了時のHDSSスコアが1又は2であり、治療終了時の両腋窩合計発汗重量のベースラインとの比が0.5 以下の被験者の割合の解析はカイ2乗検定によって行った。 <Analysis of effectiveness>
(1) Primary efficacy analysis Chi-square test is used to analyze the proportion of subjects with an HDSS score of 1 or 2 at the end of treatment and a ratio of total axillary sweating weight to baseline of 0.5 or less at the end of treatment. Went by.
(2) 有効性の副次的解析
1) 発汗重量
ベースライン1～3の両腋窩合計の発汗重量の中央値をベースラインの発汗重量とし、投与6週目1～3の両腋窩合計の発汗重量の中央値を治療終了時の両腋窩合計の発汗重量とした。
両腋窩合計の発汗重量について投与群別に実施時期ごとの基本統計量を算出し、投与群間で比較した。また、以下を算出し、投与群間の差に関して信頼区間を示し、統計学的検定を行った。
・ 治療終了時の両腋窩の合計発汗重量のベースラインとの比が0.5以下の被験者の割合
・ 治療終了時の両腋窩の合計発汗重量のベースラインからの変化量
2) HDSS
ベースライン1～3のHDSSスコアの中央値をベースラインのHDSSスコアとし、投与6週目1～3のHDSSスコアの中央値を治療終了時のHDSSスコアとした。投与群別に実施時期ごとに集計した。また、治療終了時のHDSSスコアが1又は2 の被験者の割合を算出し、投与群間の差に関して信頼区間を示し、統計学的検定を行った。 (2) Secondary analysis of effectiveness
1) 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.
-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) HDSS
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.
1) 発汗重量
ベースライン1～3の両腋窩合計の発汗重量の中央値をベースラインの発汗重量とし、投与6週目1～3の両腋窩合計の発汗重量の中央値を治療終了時の両腋窩合計の発汗重量とした。
両腋窩合計の発汗重量について投与群別に実施時期ごとの基本統計量を算出し、投与群間で比較した。また、以下を算出し、投与群間の差に関して信頼区間を示し、統計学的検定を行った。
・ 治療終了時の両腋窩の合計発汗重量のベースラインとの比が0.5以下の被験者の割合
・ 治療終了時の両腋窩の合計発汗重量のベースラインからの変化量
2) HDSS
ベースライン1～3のHDSSスコアの中央値をベースラインのHDSSスコアとし、投与6週目1～3のHDSSスコアの中央値を治療終了時のHDSSスコアとした。投与群別に実施時期ごとに集計した。また、治療終了時のHDSSスコアが1又は2 の被験者の割合を算出し、投与群間の差に関して信頼区間を示し、統計学的検定を行った。 (2) Secondary analysis of effectiveness
1) 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.
-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) HDSS
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.
＜有効性の調査項目＞
以下の項目を調査し、その結果を記録した。
(1) 発汗重量測定
1) 測定条件
・ 室温：20℃～28℃、湿度：20%RH～80%RH
2) 測定方法
あらかじめ重量を測定したろ紙を被験者の両腋窩に5分間装着させた。
その後、汗を含んだろ紙の重量を測定して発汗重量を算出した。
また、被験者ごとに午前8時から午後7時の範囲で、実施時期間の差が4時間を超えない時刻に実施した。 <Effectiveness survey items>
The following items were investigated and the results were recorded.
(1) 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.
以下の項目を調査し、その結果を記録した。
(1) 発汗重量測定
1) 測定条件
・ 室温：20℃～28℃、湿度：20%RH～80%RH
2) 測定方法
あらかじめ重量を測定したろ紙を被験者の両腋窩に5分間装着させた。
その後、汗を含んだろ紙の重量を測定して発汗重量を算出した。
また、被験者ごとに午前8時から午後7時の範囲で、実施時期間の差が4時間を超えない時刻に実施した。 <Effectiveness survey items>
The following items were investigated and the results were recorded.
(1) 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.
(2) HDSS
HDSSスコアの判定基準は以下のとおりである。
(2) HDSS
The criteria for determining the HDSS score are as follows.
HDSSスコアの判定基準は以下のとおりである。
The criteria for determining the HDSS score are as follows.
＜対象患者及び主な組入れ基準＞
同意取得時の年齢が12歳以上で、以下の診断基準及び条件を満たす原発性腋窩多汗症の患者
1. スクリーニングでの問診にて、以下の6項目のうち2項目以上に該当する、原発性腋窩多汗症と診断された患者
(1) 最初に症状がでたのが25歳以下である
(2) 左右対称性に発汗がみられる
(3) 睡眠中は発汗が止まっている
(4) 1週間に1回以上多汗のエピソードがある
(5) 家族歴がみられる
(6) 過剰な発汗により日常生活に支障をきたす
2. 以下の条件をすべて満たす患者
(1) ベースライン1～3の各時点でのHDSSスコアが3又は4
(2) ベースライン1～3の3時点のうちいずれかの2時点で、各腋窩の発汗重量がともに50 mg 以上 <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.
同意取得時の年齢が12歳以上で、以下の診断基準及び条件を満たす原発性腋窩多汗症の患者
1. スクリーニングでの問診にて、以下の6項目のうち2項目以上に該当する、原発性腋窩多汗症と診断された患者
(1) 最初に症状がでたのが25歳以下である
(2) 左右対称性に発汗がみられる
(3) 睡眠中は発汗が止まっている
(4) 1週間に1回以上多汗のエピソードがある
(5) 家族歴がみられる
(6) 過剰な発汗により日常生活に支障をきたす
2. 以下の条件をすべて満たす患者
(1) ベースライン1～3の各時点でのHDSSスコアが3又は4
(2) ベースライン1～3の3時点のうちいずれかの2時点で、各腋窩の発汗重量がともに50 mg 以上 <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.
＜主な除外基準＞
1. 続発性多汗症患者
2. 閉経により多汗症状が開始又は悪化した患者
3. 胸部交感神経遮断術の適応となる患者 <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
1. 続発性多汗症患者
2. 閉経により多汗症状が開始又は悪化した患者
3. 胸部交感神経遮断術の適応となる患者 <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
＜治験対象患者＞
原発性腋窩多汗症患者281名に治験薬を無作為に割り付け（0%群140名、5%群141名）、これら患者群を対象としてデータ解析を行った。 <Patients subject to clinical trials>
The study drug was randomly assigned to 281 patients with primary axillary hyperhidrosis (140 in the 0% group and 141 in the 5% group), and data analysis was performed on these patient groups.
原発性腋窩多汗症患者281名に治験薬を無作為に割り付け（0%群140名、5%群141名）、これら患者群を対象としてデータ解析を行った。 <Patients subject to clinical trials>
The study drug was randomly assigned to 281 patients with primary axillary hyperhidrosis (140 in the 0% group and 141 in the 5% group), and data analysis was performed on these patient groups.
＜有効性の主要評価項目の結果＞
治療終了時のHDSSスコアが1又は2であり、治療終了時の両腋窩合計発汗重量のベースラインとの比が0.5以下の被験者の割合を下表に示した。 <Results of primary efficacy endpoint>
The table below shows the proportion of subjects with an HDSS score of 1 or 2 at the end of treatment and a ratio of total axillary sweating weight to baseline of 0.5 or less at the end of treatment.
治療終了時のHDSSスコアが1又は2であり、治療終了時の両腋窩合計発汗重量のベースラインとの比が0.5以下の被験者の割合を下表に示した。 <Results of primary efficacy endpoint>
The table below shows the proportion of subjects with an HDSS score of 1 or 2 at the end of treatment and a ratio of total axillary sweating weight to baseline of 0.5 or less at the end of treatment.
＜有効性の副次的評価項目の結果＞
(1) HDSS
治療終了時のHDSSスコアが1又は2の被験者の割合は、0%群で47.9%（67/140名）、5%群で60.3%（85/141名）であった。0%群より5%群が12.4%（95%信頼区間：0.86～23.99）高く、群間に統計学的な有意差がみられた（カイ2乗検定：p = 0.036）。 <Results of secondary evaluation items for effectiveness>
(1) HDSS
The proportion of subjects with an HDSS score of 1 or 2 at the end of treatment was 47.9% (67/140) in the 0% group and 60.3% (85/141) in the 5% group. The 5% group was 12.4% (95% confidence interval: 0.86 to 23.99) higher than the 0% group, and there was a statistically significant difference between the groups (chi-square test: p = 0.036).
(1) HDSS
治療終了時のHDSSスコアが1又は2の被験者の割合は、0%群で47.9%（67/140名）、5%群で60.3%（85/141名）であった。0%群より5%群が12.4%（95%信頼区間：0.86～23.99）高く、群間に統計学的な有意差がみられた（カイ2乗検定：p = 0.036）。 <Results of secondary evaluation items for effectiveness>
(1) HDSS
The proportion of subjects with an HDSS score of 1 or 2 at the end of treatment was 47.9% (67/140) in the 0% group and 60.3% (85/141) in the 5% group. The 5% group was 12.4% (95% confidence interval: 0.86 to 23.99) higher than the 0% group, and there was a statistically significant difference between the groups (chi-square test: p = 0.036).
(2) 発汗重量
治療終了時の両腋窩合計発汗重量のベースラインとの比が0.5以下の被験者の割合は、0%群で66.4%（93/140名）、5%群で77.3%（109/141名）であった。0%群より5%群が10.9%（95%信頼区間：0.44～21.32）高く、群間に統計学的な有意差がみられた（カイ2乗検定：p = 0.042）。 (2) Sweat weight The proportion of subjects whose total axillary sweat weight ratio to baseline at the end of treatment was 0.5 or less was 66.4% (93/140 subjects) in the 0% group and 77.3% (109) in the 5% group. / 141 people). The 5% group was 10.9% (95% confidence interval: 0.44 to 21.32) higher than the 0% group, and there was a statistically significant difference between the groups (chi-square test: p = 0.042).
治療終了時の両腋窩合計発汗重量のベースラインとの比が0.5以下の被験者の割合は、0%群で66.4%（93/140名）、5%群で77.3%（109/141名）であった。0%群より5%群が10.9%（95%信頼区間：0.44～21.32）高く、群間に統計学的な有意差がみられた（カイ2乗検定：p = 0.042）。 (2) Sweat weight The proportion of subjects whose total axillary sweat weight ratio to baseline at the end of treatment was 0.5 or less was 66.4% (93/140 subjects) in the 0% group and 77.3% (109) in the 5% group. / 141 people). The 5% group was 10.9% (95% confidence interval: 0.44 to 21.32) higher than the 0% group, and there was a statistically significant difference between the groups (chi-square test: p = 0.042).
＜両腋窩合計発汗重量が400 mg以上の患者での有効性の結果＞
ベースラインの両腋窩合計発汗重量発汗の程度が重症の患者での有効性を検討するため、ベースラインの両腋窩合計発汗重量が400 mg以上の患者を対象とした部分集団での有効性を検討した。
解析結果を下表に示した。 <Results of efficacy in patients with a total axillary sweating weight of 400 mg or more>
Efficacy in patients with severe baseline biaxillary sweating weight was examined in a subpopulation of patients with baseline biaxillary total sweating weight of 400 mg or more. bottom.
The analysis results are shown in the table below.
ベースラインの両腋窩合計発汗重量発汗の程度が重症の患者での有効性を検討するため、ベースラインの両腋窩合計発汗重量が400 mg以上の患者を対象とした部分集団での有効性を検討した。
解析結果を下表に示した。 <Results of efficacy in patients with a total axillary sweating weight of 400 mg or more>
Efficacy in patients with severe baseline biaxillary sweating weight was examined in a subpopulation of patients with baseline biaxillary total sweating weight of 400 mg or more. bottom.
The analysis results are shown in the table below.
主要評価項目である「治療終了時のHDSSスコアが1又は2であり、治療終了時の両腋窩合計発汗重量のベースラインとの比が0.5以下の被験者の割合」は、いずれのカテゴリーでも0%群より5%群で高かった。また、群間差は、100 mg以上400 mg未満のカテゴリーで15.5%、400 mg以上のカテゴリーで46.2%であった。すなわち、群間差は、400 mg以上のカテゴリーでより大きかった。
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.
「治療終了時のHDSSスコアが1又は2の被験者の割合」及び「治療終了時の両腋窩合計発汗重量のベースラインとの比が0.5以下の被験者の割合」はいずれのカテゴリーでも0%群より5%群で高かった。両腋窩合計発汗重量の平均値は、いずれのカテゴリー及び投与後の各評価時点でも0%群より5%群が小さかった。治療終了時の両腋窩合計発汗重量の平均値は、いずれのカテゴリーでも0%群より5%群が小さかった。
以上、ベースラインの両腋窩合計発汗重量が400 mg以上験者で、いずれの評価項目でも0%群より5%群で改善がみられた。 "Percentage of subjects with HDSS score of 1 or 2 at the end of treatment" and "Proportion of subjects with a ratio of total axillary sweat weight to baseline of 0.5 or less at the end of treatment" were from the 0% group in all categories. It was high in the 5% group. The mean value of the total sweating weight of both axillae was smaller in the 5% group than in the 0% group at each evaluation time in each category and after administration. The mean total sweating weight of both axillae at the end of treatment was smaller in the 5% group than in the 0% group in all categories.
As mentioned above, the total sweating weight of both axillae at baseline was 400 mg or more, and improvement was observed in the 5% group from the 0% group in all the endpoints.
以上、ベースラインの両腋窩合計発汗重量が400 mg以上験者で、いずれの評価項目でも0%群より5%群で改善がみられた。 "Percentage of subjects with HDSS score of 1 or 2 at the end of treatment" and "Proportion of subjects with a ratio of total axillary sweat weight to baseline of 0.5 or less at the end of treatment" were from the 0% group in all categories. It was high in the 5% group. The mean value of the total sweating weight of both axillae was smaller in the 5% group than in the 0% group at each evaluation time in each category and after administration. The mean total sweating weight of both axillae at the end of treatment was smaller in the 5% group than in the 0% group in all categories.
As mentioned above, the total sweating weight of both axillae at baseline was 400 mg or more, and improvement was observed in the 5% group from the 0% group in all the endpoints.
＜5% BBI-4000群における治療前後のHDSSスコアの変化量＞
原発性腋窩多汗症患者を対象とした無作為化二重盲検並行群間比較により、5%のBBI-4000を1日1回、6週間、腋窩に塗布した際、各被検者の治療前のHDSSスコアから治療終了時のHDSSスコアを減算し、その差（ΔHDSS）を算出した。治療前と治療終了時の両HDSSスコアを得られた140例を解析対象とし、ΔHDSSの平均変化量と標準偏差を算出した。
その結果、5% BBI-4000群の平均ΔHDSSは1.14±0.87であった。 <Changes in HDSS score before and after treatment in the 5% BBI-4000 group>
A randomized, double-blind, parallel-group comparison of patients with primary axillary hyperhidrosis showed that 5% of BBI-4000 was applied to the axilla once daily for 6 weeks for each subject. The HDSS score at the end of treatment was subtracted from the HDSS score before treatment, and the difference (ΔHDSS) was calculated. The mean change and standard deviation of ΔHDSS were calculated for 140 patients who obtained both HDSS scores before and after treatment.
As a result, the mean ΔHDSS of the 5% BBI-4000 group was 1.14 ± 0.87.
原発性腋窩多汗症患者を対象とした無作為化二重盲検並行群間比較により、5%のBBI-4000を1日1回、6週間、腋窩に塗布した際、各被検者の治療前のHDSSスコアから治療終了時のHDSSスコアを減算し、その差（ΔHDSS）を算出した。治療前と治療終了時の両HDSSスコアを得られた140例を解析対象とし、ΔHDSSの平均変化量と標準偏差を算出した。
その結果、5% BBI-4000群の平均ΔHDSSは1.14±0.87であった。 <Changes in HDSS score before and after treatment in the 5% BBI-4000 group>
A randomized, double-blind, parallel-group comparison of patients with primary axillary hyperhidrosis showed that 5% of BBI-4000 was applied to the axilla once daily for 6 weeks for each subject. The HDSS score at the end of treatment was subtracted from the HDSS score before treatment, and the difference (ΔHDSS) was calculated. The mean change and standard deviation of ΔHDSS were calculated for 140 patients who obtained both HDSS scores before and after treatment.
As a result, the mean ΔHDSS of the 5% BBI-4000 group was 1.14 ± 0.87.
［試験例2］
原発性腋窩多汗症患者を対象としたBBI-4000 の長期投与試験
上記検証試験（試験例１）に参加した被験者を含む日本人の原発性腋窩多汗症患者を対象に、5% BBI-4000（試験例１と同じ）を1日1回就寝前に52週間投与した際の安全性及び有効性を検討した。
試験デザインは、非対照、かつ、オープンとした。 [Test Example 2]
Long-term administration study of BBI-4000 in patients with primaryaxillary 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.
原発性腋窩多汗症患者を対象としたBBI-4000 の長期投与試験
上記検証試験（試験例１）に参加した被験者を含む日本人の原発性腋窩多汗症患者を対象に、5% BBI-4000（試験例１と同じ）を1日1回就寝前に52週間投与した際の安全性及び有効性を検討した。
試験デザインは、非対照、かつ、オープンとした。 [Test Example 2]
Long-term administration study of BBI-4000 in patients with primary
The study design was uncontrolled and open.
＜主な組入れ基準＞
以下の基準をすべて満たす患者を組み入れた。
1. 試験例1において6週間の治療期間を完了した被験者
2. 試験例1で治験薬の使用率が80%以上であった被験者 <Main inclusion criteria>
Patients who met all of the following criteria were enrolled.
1. Subjects who completed a 6-week treatment period in Test Example 1
2. Subjects whose study drug usage rate was 80% or higher in Study Example 1
以下の基準をすべて満たす患者を組み入れた。
1. 試験例1において6週間の治療期間を完了した被験者
2. 試験例1で治験薬の使用率が80%以上であった被験者 <Main inclusion criteria>
Patients who met all of the following criteria were enrolled.
1. Subjects who completed a 6-week treatment period in Test Example 1
2. Subjects whose study drug usage rate was 80% or higher in Study Example 1
＜主な有効性の評価項目＞
(1) HDSSスコアが1又は2であり、両腋窩合計発汗重量の比が0.5以下の被験者の割合
(2) HDSSスコアが1又は2の被験者の割合
(3) 両腋窩合計発汗重量の比が0.5以下の被験者の割合
(4) 両腋窩発汗重量の変化量 <Main efficacy evaluation items>
(1) Percentage of subjects with an HDSS score of 1 or 2 and a ratio of total axillary sweating weight of 0.5 or less
(2) Percentage of subjects with an HDSS score of 1 or 2
(3) Percentage of subjects with a total axillary sweating weight ratio of 0.5 or less
(4) Change in biaxillary sweating weight
(1) HDSSスコアが1又は2であり、両腋窩合計発汗重量の比が0.5以下の被験者の割合
(2) HDSSスコアが1又は2の被験者の割合
(3) 両腋窩合計発汗重量の比が0.5以下の被験者の割合
(4) 両腋窩発汗重量の変化量 <Main efficacy evaluation items>
(1) Percentage of subjects with an HDSS score of 1 or 2 and a ratio of total axillary sweating weight of 0.5 or less
(2) Percentage of subjects with an HDSS score of 1 or 2
(3) Percentage of subjects with a total axillary sweating weight ratio of 0.5 or less
(4) Change in biaxillary sweating weight
＜治験対象患者＞
上記の試験例1から移行した原発性腋窩多汗症患者185名（試験例1の0%群：94名（以下、0%/5%群）、試験1の5%群91名（以下、5%/5%群））に休薬期間を設けずに、試験例１と同じソフピロニウム臭化物含有外用医薬製剤（5% BBI-4000）を投与した。 <Patients subject to clinical trials>
185 patients with primary axillary hyperhidrosis who migrated from Test Example 1 above (0% group of Test Example 1: 94 patients (hereinafter, 0% / 5% group), 91 patients of 5% group of Study 1 (hereinafter, below) The same sofpironium bromide-containing topical pharmaceutical preparation (5% BBI-4000) as in Test Example 1 was administered to 5% / 5% group)) without a drug holiday.
上記の試験例1から移行した原発性腋窩多汗症患者185名（試験例1の0%群：94名（以下、0%/5%群）、試験1の5%群91名（以下、5%/5%群））に休薬期間を設けずに、試験例１と同じソフピロニウム臭化物含有外用医薬製剤（5% BBI-4000）を投与した。 <Patients subject to clinical trials>
185 patients with primary axillary hyperhidrosis who migrated from Test Example 1 above (0% group of Test Example 1: 94 patients (hereinafter, 0% / 5% group), 91 patients of 5% group of Study 1 (hereinafter, below) The same sofpironium bromide-containing topical pharmaceutical preparation (5% BBI-4000) as in Test Example 1 was administered to 5% / 5% group)) without a drug holiday.
＜有効性に関する解析＞
治療終了時のHDSSスコアが1又は2であり、治療終了時の両腋窩合計発汗重量のベースラインとの比が0.5 以下の被験者の割合を算出した。本試験におけるベースラインは、試験例１のベースライン3でのHDSSスコア及び発汗重量とした。また、治療終了時のHDSSスコアと発汗重量は、試験例１から移行後52週目に測定した値とした。 <Analysis of effectiveness>
The proportion of subjects with an HDSS score of 1 or 2 at the end of treatment and a ratio of total axillary sweating weight to baseline at the end of treatment was calculated. The baseline in this test was the HDSS score and sweating weight at baseline 3 of Test Example 1. The HDSS score and sweating weight at the end of treatment were measured 52 weeks after the transition from Test Example 1.
治療終了時のHDSSスコアが1又は2であり、治療終了時の両腋窩合計発汗重量のベースラインとの比が0.5 以下の被験者の割合を算出した。本試験におけるベースラインは、試験例１のベースライン3でのHDSSスコア及び発汗重量とした。また、治療終了時のHDSSスコアと発汗重量は、試験例１から移行後52週目に測定した値とした。 <Analysis of effectiveness>
The proportion of subjects with an HDSS score of 1 or 2 at the end of treatment and a ratio of total axillary sweating weight to baseline at the end of treatment was calculated. The baseline in this test was the HDSS score and sweating weight at baseline 3 of Test Example 1. The HDSS score and sweating weight at the end of treatment were measured 52 weeks after the transition from Test Example 1.
＜有効性の結果＞
治療終了時のHDSSスコアが1又は2であり、治療終了時の両腋窩合計発汗重量のベースラインとの比が0.5以下の被験者の割合を下表に示した。 <Result of effectiveness>
The table below shows the proportion of subjects with an HDSS score of 1 or 2 at the end of treatment and a ratio of total axillary sweating weight to baseline of 0.5 or less at the end of treatment.
治療終了時のHDSSスコアが1又は2であり、治療終了時の両腋窩合計発汗重量のベースラインとの比が0.5以下の被験者の割合を下表に示した。 <Result of effectiveness>
The table below shows the proportion of subjects with an HDSS score of 1 or 2 at the end of treatment and a ratio of total axillary sweating weight to baseline of 0.5 or less at the end of treatment.
試験例１から移行後52週目のHDSSスコアが1又は2であり、両腋窩合計発汗重量の試験例1のベースラインとの比が0.5以下の被験者の割合は、0%/5%群57.4%（54/94名）、5%/5%群58.2%（53/91名）であった。
さらに、試験例１から移行後52週目のHDSSスコアが1又は2の被験者の割合は、0%/5%群76.6%（72/94名）、5%/5%群71.4%（65/91名）であった。
試験例１から移行後52週目の両腋窩合計発汗重量のベースラインとの比が0.5以下の被験者の割合は、0%/5%群66.6%（62/94名）、5%/5%群67.0%（61/91名）であった。
試験例１から移行後52週目の両腋窩合計発汗重量のベースラインからの変化量の平均値±標準偏差は、0%/5%群 -157.7±178.08 mg、5%/5%群 -141.6±168.47 mgであった。 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.
さらに、試験例１から移行後52週目のHDSSスコアが1又は2の被験者の割合は、0%/5%群76.6%（72/94名）、5%/5%群71.4%（65/91名）であった。
試験例１から移行後52週目の両腋窩合計発汗重量のベースラインとの比が0.5以下の被験者の割合は、0%/5%群66.6%（62/94名）、5%/5%群67.0%（61/91名）であった。
試験例１から移行後52週目の両腋窩合計発汗重量のベースラインからの変化量の平均値±標準偏差は、0%/5%群 -157.7±178.08 mg、5%/5%群 -141.6±168.47 mgであった。 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.
治療中の有害事象は、おおむね軽度であった。従って、5% BBI-4000は少なくとも52週間投与まで有効性が持続し、安全性上のリスクもコントロール可能であった。
Adverse events during treatment were generally mild. Therefore, 5% BBI-4000 remained effective for at least 52 weeks and the safety risk was controllable.
［試験例3］
様々なソフピロニウム臭化物製剤における粘度安定性試験
＜調液方法＞
各製剤は、ソフピロニウム臭化物、無水クエン酸、ミリスチン酸イソプロピル（2.5w/w%）、へキシレングリコール(10w/w%)、ヒドロキシプロピルセルロース(1.25w/w%)を含有する製剤である。ソフピロニウム臭化物、および無水クエン酸の濃度は表6に示した。全量が100％となるように、残分は無水エタノールで構成される。配合成分を無水エタノールに攪拌・溶解し各製剤を調製した。 [Test Example 3]
Viscosity stability test for various sofpironium bromide preparations <Liquid preparation method>
Each preparation contains sofpironium bromide, citric acid anhydride, isopropyl myristate (2.5 w / w%), hexylene glycol (10 w / w%), and hydroxypropyl cellulose (1.25 w / w%). The concentrations of sofpironium bromide and citric acid anhydride are shown in Table 6. The balance is composed of absolute ethanol so that the total amount is 100%. Each preparation was prepared by stirring and dissolving the ingredients in absolute ethanol.
様々なソフピロニウム臭化物製剤における粘度安定性試験
＜調液方法＞
各製剤は、ソフピロニウム臭化物、無水クエン酸、ミリスチン酸イソプロピル（2.5w/w%）、へキシレングリコール(10w/w%)、ヒドロキシプロピルセルロース(1.25w/w%)を含有する製剤である。ソフピロニウム臭化物、および無水クエン酸の濃度は表6に示した。全量が100％となるように、残分は無水エタノールで構成される。配合成分を無水エタノールに攪拌・溶解し各製剤を調製した。 [Test Example 3]
Viscosity stability test for various sofpironium bromide preparations <Liquid preparation method>
Each preparation contains sofpironium bromide, citric acid anhydride, isopropyl myristate (2.5 w / w%), hexylene glycol (10 w / w%), and hydroxypropyl cellulose (1.25 w / w%). The concentrations of sofpironium bromide and citric acid anhydride are shown in Table 6. The balance is composed of absolute ethanol so that the total amount is 100%. Each preparation was prepared by stirring and dissolving the ingredients in absolute ethanol.
＜粘度測定方法＞
粘度計を25℃、毎分10 rpm、プレヒート時間：30秒に設定し、約1 mLをコーンロータ：R-H1°34’×R24で200秒回転させた後の値を測定した（日本薬局方粘度測定法第2法）。 <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).
粘度計を25℃、毎分10 rpm、プレヒート時間：30秒に設定し、約1 mLをコーンロータ：R-H1°34’×R24で200秒回転させた後の値を測定した（日本薬局方粘度測定法第2法）。 <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).
調液時の粘度に対して、調液後40℃で3か月保管後における粘度の増減率（％）を計算し、±30％以内の場合を「A」、±30％を超える場合を「B」と判定した。結果を下表に示す。
なお、下表のpHは、保存期間（調液後から3か月目まで）における最高値を示した。 For the viscosity at the time of liquid preparation, calculate the rate of increase / decrease (%) of the viscosity after storage at 40 ° C for 3 months after liquid preparation, and if it is within ± 30%, it is "A", and if it exceeds ± 30%, it is Judged as "B". The results are shown in the table below.
The pH in the table below showed the highest value during the storage period (from the liquid preparation to the third month).
なお、下表のpHは、保存期間（調液後から3か月目まで）における最高値を示した。 For the viscosity at the time of liquid preparation, calculate the rate of increase / decrease (%) of the viscosity after storage at 40 ° C for 3 months after liquid preparation, and if it is within ± 30%, it is "A", and if it exceeds ± 30%, it is Judged as "B". The results are shown in the table below.
The pH in the table below showed the highest value during the storage period (from the liquid preparation to the third month).
全製剤量に対して0.001w/w%のクエン酸を添加した場合、pHが5.5となり、ソフピロニウム臭化物製剤の経時的な粘度の低下は著しかった（比較例1）。一方、全製剤量に対して0.015w/w%から0.1w/w%未満の無水クエン酸を添加した場合、pHが5.2以下となり、経時的な粘度の低下は、軽微であるか、観察されなかった（実施例１～４）。
When 0.001 w / w% citric acid was added to the total amount of the product, the pH became 5.5, and the viscosity of the sofpironium bromide product decreased significantly over time (Comparative Example 1). On the other hand, when anhydrous citric acid of 0.015 w / w% to less than 0.1 w / w% is added to the total amount of the product, the pH becomes 5.2 or less, and the decrease in viscosity over time is observed to be slight. No (Examples 1 to 4).
［試験例4］
ソフピロニウム臭化物製剤の長期保存試験 [Test Example 4]
Long-term storage test of sofpironium bromide preparation
ソフピロニウム臭化物製剤の長期保存試験 [Test Example 4]
Long-term storage test of sofpironium bromide preparation
＜調液方法＞
試験例3と同様の方法で、下表の実施例５、実施例６、比較例2、及び比較例3を調液し、各種試験に用いた。表中の構成成分と濃度となるように、配合成分を無水エタノールに攪拌・溶解し製剤を得た。本法で製造した各製剤の内容を下表に示す。 <Liquid preparation method>
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.
試験例3と同様の方法で、下表の実施例５、実施例６、比較例2、及び比較例3を調液し、各種試験に用いた。表中の構成成分と濃度となるように、配合成分を無水エタノールに攪拌・溶解し製剤を得た。本法で製造した各製剤の内容を下表に示す。 <Liquid preparation method>
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.
** q.s. to 100: 全量が100%となるように、残分は無水エタノールで構成される。
** qs to 100: The balance is composed of absolute ethanol so that the total amount is 100%.
＜試験方法＞
pH測定方法、及び粘度測定方法は、試験例３と同様である。 <Test method>
The pH measuring method and the viscosity measuring method are the same as those in Test Example 3.
pH測定方法、及び粘度測定方法は、試験例３と同様である。 <Test method>
The pH measuring method and the viscosity measuring method are the same as those in Test Example 3.
＜安定性試験方法1：25℃±2℃／60%RH±5%RH、遮光、24か月間の保存＞
実施例５と実施例６の製剤は、安定性試験１に用いた。下表のpHは、保存期間（即ち、調液してから24か月目まで）における最高値を示した。表中の判定基準は、試験例3と同義である。比較例2は、同様に6か月間保存した。 <Stability test method 1: 25 ° C ± 2 ° C / 60% RH ± 5% RH, shading, storage for 24 months>
The formulations of Example 5 and Example 6 were used in Stability Test 1. The pH in the table below showed the highest value during the storage period (that is, up to the 24th month after the liquid was prepared). The criteria in the table are synonymous with Test Example 3. Comparative Example 2 was similarly stored for 6 months.
実施例５と実施例６の製剤は、安定性試験１に用いた。下表のpHは、保存期間（即ち、調液してから24か月目まで）における最高値を示した。表中の判定基準は、試験例3と同義である。比較例2は、同様に6か月間保存した。 <Stability test method 1: 25 ° C ± 2 ° C / 60% RH ± 5% RH, shading, storage for 24 months>
The formulations of Example 5 and Example 6 were used in Stability Test 1. The pH in the table below showed the highest value during the storage period (that is, up to the 24th month after the liquid was prepared). The criteria in the table are synonymous with Test Example 3. Comparative Example 2 was similarly stored for 6 months.
＜安定性試験方法2：30℃±2℃／60%RH±5%RH、遮光、12か月間の保存＞
比較例3の製剤は、安定性試験２に用いた。下表のpHは、保存期間（即ち、調液してから12か月目まで）における最高値を示した。表中の判定基準は、試験例3と同義である。 <Stability test method 2: 30 ° C ± 2 ° C / 60% RH ± 5% RH, shading, storage for 12 months>
The formulation of Comparative Example 3 was used for stability test 2. The pH in the table below showed the highest value during the storage period (that is, up to the 12th month after the liquid was prepared). The criteria in the table are synonymous with Test Example 3.
比較例3の製剤は、安定性試験２に用いた。下表のpHは、保存期間（即ち、調液してから12か月目まで）における最高値を示した。表中の判定基準は、試験例3と同義である。 <Stability test method 2: 30 ° C ± 2 ° C / 60% RH ± 5% RH, shading, storage for 12 months>
The formulation of Comparative Example 3 was used for stability test 2. The pH in the table below showed the highest value during the storage period (that is, up to the 12th month after the liquid was prepared). The criteria in the table are synonymous with Test Example 3.
無水クエン酸濃度が0.001w/w%の比較例2と比較例3の製剤は、調液時のpHは6.1～5.9であり、室温下で保存した場合、pHは経時的に変動した。
無水クエン酸濃度が0.001w/w%の比較例3の製剤は、室温下で12か月保存すると顕著に粘度が低下した(-76%)。一方、無水クエン酸濃度が0.05w/w%の実施例５、６の製剤は、調液後のpHが5.2以下に維持されており、粘度の経時的な変動は僅かであった。
したがって、調液してからpHが5.2以下に維持されるソフピロニウム臭化物製剤は、経時的な粘度の低下を抑制することができる。
特に、本試験により、室温で製剤が保存された場合において、調液してから6か月目までのいずれかの時点のpHが2.5から5.2の製剤が好ましいことが明らかとなった。例えば、室温で製剤が保存された場合の、調液してから１か月目、3か月目、又は6か月目のpHが2.5から5.2の範囲内である製剤が好ましい。 The formulations of 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. On the other hand, in the formulations of Examples 5 and 6 having an anhydrous citric acid concentration of 0.05 w / w%, the pH after preparation was maintained at 5.2 or less, and the change in viscosity with time was slight.
Therefore, 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.
In particular, 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. For example, when the preparation is stored at room temperature, 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.
無水クエン酸濃度が0.001w/w%の比較例3の製剤は、室温下で12か月保存すると顕著に粘度が低下した(-76%)。一方、無水クエン酸濃度が0.05w/w%の実施例５、６の製剤は、調液後のpHが5.2以下に維持されており、粘度の経時的な変動は僅かであった。
したがって、調液してからpHが5.2以下に維持されるソフピロニウム臭化物製剤は、経時的な粘度の低下を抑制することができる。
特に、本試験により、室温で製剤が保存された場合において、調液してから6か月目までのいずれかの時点のpHが2.5から5.2の製剤が好ましいことが明らかとなった。例えば、室温で製剤が保存された場合の、調液してから１か月目、3か月目、又は6か月目のpHが2.5から5.2の範囲内である製剤が好ましい。 The formulations of 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. On the other hand, in the formulations of Examples 5 and 6 having an anhydrous citric acid concentration of 0.05 w / w%, the pH after preparation was maintained at 5.2 or less, and the change in viscosity with time was slight.
Therefore, 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.
In particular, 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. For example, when the preparation is stored at room temperature, 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.
＜純度試験＞
実施例５と実施例６の製剤の長期保存試験（25℃±2℃／60%RH±5%RH、遮光）において、調液してから24か月目まで純度試験（類縁物質）を実施した。実施例５において、24か月目にシクロペンチルマンデル酸エチルのHPLCピークがごく僅かに観察された。実施例６においては、調液してから保存期間中に類縁物質の増加及び新たな類縁物質の出現は認められなかった。これらの結果から、実施例５と実施例６の製剤が長期保存試験において安定であることが示された。 <Purity test>
In the long-term storage test (25 ° C ± 2 ° C / 60% RH ± 5% RH, shading) of the formulations of Examples 5 and 6, a purity test (related substance) was carried out until 24 months after the liquid was prepared. bottom. In Example 5, a very slight HPLC peak of ethyl cyclopentyl mandelate was observed at 24 months. In Example 6, no increase in related substances and appearance of new related substances were observed during the storage period after the liquid was prepared. From these results, it was shown that the formulations of Example 5 and Example 6 are stable in the long-term storage test.
実施例５と実施例６の製剤の長期保存試験（25℃±2℃／60%RH±5%RH、遮光）において、調液してから24か月目まで純度試験（類縁物質）を実施した。実施例５において、24か月目にシクロペンチルマンデル酸エチルのHPLCピークがごく僅かに観察された。実施例６においては、調液してから保存期間中に類縁物質の増加及び新たな類縁物質の出現は認められなかった。これらの結果から、実施例５と実施例６の製剤が長期保存試験において安定であることが示された。 <Purity test>
In the long-term storage test (25 ° C ± 2 ° C / 60% RH ± 5% RH, shading) of the formulations of Examples 5 and 6, a purity test (related substance) was carried out until 24 months after the liquid was prepared. bottom. In Example 5, a very slight HPLC peak of ethyl cyclopentyl mandelate was observed at 24 months. In Example 6, no increase in related substances and appearance of new related substances were observed during the storage period after the liquid was prepared. From these results, it was shown that the formulations of Example 5 and Example 6 are stable in the long-term storage test.
以上のように、保存温度等の試験条件によらず、実施例５と実施例６で示されたように、pHが5.2以下に維持されるソフピロニウム臭化物製剤は、長期間にわたり不純物増加がみられず、かつ、粘度の低下が抑制されることが明らかとなった。
As described above, as shown in Examples 5 and 6, the sofpironium bromide preparation whose pH is maintained at 5.2 or less shows an increase in impurities over a long period of time regardless of the test conditions such as the storage temperature. However, it was clarified that the decrease in viscosity was suppressed.
本発明によれば、ソフピロニウム臭化物の医薬製剤を治療前の両腋窩合計発汗重量が100 mg以上である原発性腋窩多汗症、特に、治療前の両腋窩合計発汗重量が400 mg以上である重症の原発性腋窩多汗症に対する治療に用いることができる。
According to the present invention, 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.
Claims (16)
- ソフピロニウム臭化物を有効成分として含み、1日1回、両腋窩に塗布するための医薬製剤であって、治療前の5分間の重量測定法による両腋窩合計発汗重量が400 mg以上である原発性腋窩多汗症を治療するための製剤。 A pharmaceutical preparation containing sofpironium bromide as an active ingredient and applied to both axillas once a day. The total sweating weight of both axillas by a 5-minute weight measurement method before treatment is 400 mg or more. A preparation for treating hyperhidrosis.
- ソフピロニウム臭化物の含有量が、全製剤量に対して、5w/w%から15w/w%である、請求項1に記載の製剤。 The preparation according to claim 1, wherein the content of the sofpironium bromide is 5 w / w% to 15 w / w% with respect to the total amount of the preparation.
- ソフピロニウム臭化物の含有量が、全製剤量に対して、5w/w%である、請求項1又は請求項2に記載の製剤。 The preparation according to claim 1 or 2, wherein the content of the sofpironium bromide is 5 w / w% with respect to the total amount of the preparation.
- 各腋窩へ投与される製剤の一回の投与あたりの平均量が、0.5 mLから1.0 mLであることを特徴とする、請求項1から請求項3のいずれか一つに記載の製剤。 The preparation according to any one of claims 1 to 3, wherein the average amount of the preparation to be administered to each axilla per administration is 0.5 mL to 1.0 mL.
- 投与される一回の投与あたりのソフロピロニウム臭化物の平均量が、腋窩の身体表面1cm2あたり、5.0 μgから2000 μgであることを特徴とする、請求項1から請求項4のいずれか一つに記載の製剤。 The average amount of Sofuropironiumu bromide per single administration to be administered, the body surface 1 cm 2 per axilla, characterized in that from 5.0 [mu] g is 2000 [mu] g, to any one of claims 1 to 4 The described formulation.
- 治療前と比較して、治療期間中又は治療後にHDSSスコアを1以上低下させる制汗作用を有することを特徴とする、請求項1から請求項5のいずれか一つに記載の製剤。 The preparation according to any one of claims 1 to 5, which has an antiperspirant action that lowers the HDSS score by 1 or more during or after the treatment as compared with before the treatment.
- 前記原発性腋窩多汗症が、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症である、請求項1から前記請求項6のいずれか一つに記載の製剤。 The preparation according to any one of claims 1 to 6, wherein the primary axillary hyperhidrosis is a severe primary axillary hyperhidrosis having an HDSS score of 3 or 4 before treatment.
- 前記原発性腋窩多汗症が、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症であり、治療終了時のHDSSスコアが1または2に改善することを特徴とする、請求項1から請求項7のいずれか一つに記載の製剤。 Claimed that the primary axillary hyperhidrosis is a severe primary axillary hyperhidrosis with a pretreatment HDSS score of 3 or 4 and an HDSS score of 1 or 2 at the end of treatment. The preparation according to any one of items 1 to 7.
- 前記原発性腋窩多汗症が、治療前のHDSSスコアが3又は4の重症の原発性腋窩多汗症であり、治療終了時のHDSSスコアが1または2に改善し、かつ、治療終了時の両腋窩合計発汗重量の治療前の両腋窩合計発汗重量との比が0.5以下に改善することを特徴とする、請求項1から請求項8のいずれか一つに記載の製剤。 The primary axillary hyperhidrosis is severe primary axillary hyperhidrosis with a pretreatment HDSS score of 3 or 4, and the HDSS score at the end of treatment improves to 1 or 2 and at the end of treatment. The preparation according to any one of claims 1 to 8, wherein the ratio of the total sweat weight of both axilla to the total sweat weight of both axilla before treatment is improved to 0.5 or less.
- 治療期間中に交感神経遮断術を実施することなく原発性腋窩多汗症を治療することができることを特徴とする、請求項1から請求項9のいずれか一つに記載の製剤。 The preparation according to any one of claims 1 to 9, wherein the primary axillary hyperhidrosis can be treated without performing sympathetic nerve blockade during the treatment period.
- ソフピロニウム臭化物の医薬製剤が少なくとも6週間の治療期間にわたって１日１回投与されることを特徴とする、請求項1から請求項10のいずれか一つに記載の製剤。 The preparation according to any one of claims 1 to 10, wherein the pharmaceutical preparation of sofpironium bromide is administered once a day for a treatment period of at least 6 weeks.
- ソフピロニウム臭化物の医薬製剤が6週間から52週間の治療期間にわたって１日１回投与されることを特徴とする、請求項1から請求項10のいずれか一つに記載の製剤。 The preparation according to any one of claims 1 to 10, wherein the pharmaceutical preparation of sofpironium bromide is administered once a day for a treatment period of 6 to 52 weeks.
- 全製剤量に対し5w/w％のソフピロニウム臭化物を有効成分として含み、両腋窩に、6週間を超えて52週間の治療期間にわたって１日１回投与されることを特徴とする、塗布するための医薬製剤であって、治療前の5分間の重量測定法による両腋窩合計発汗重量が100 mg以上である原発性腋窩多汗症を治療するための製剤。 It contains 5 w / w% of sofpironium bromide as an active ingredient with respect to the total amount of the drug, and is administered to both axillas once a day for a treatment period of more than 6 weeks and 52 weeks. A pharmaceutical product for treating primary axillary hyperhidrosis in which the total sweating weight of both axilla is 100 mg or more by a 5-minute weight measurement method before treatment.
- pHが5.2以下である、請求項1から請求項13のいずれか一つに記載の製剤。 The preparation according to any one of claims 1 to 13, wherein the pH is 5.2 or less.
- 全製剤量に対して0.015w/w%から0.1w/w%未満の無水クエン酸を含む、請求項1から請求項14のいずれか一つに記載の製剤。 The preparation according to any one of claims 1 to 14, which comprises 0.015 w / w% to less than 0.1 w / w% anhydrous citric acid with respect to the total amount of the preparation.
- ソフピロニウム臭化物の医薬製剤が、全製剤量に対して1.25w/w%のヒドロキシプロピルセルロースと、2.5w/w%のミリスチン酸イソプロピルと、0.05w/w%の無水クエン酸と、10w/w%のへキシレングリコールと、無水エタノールが残分として構成される、請求項1から請求項14のいずれか一つに記載の製剤。 The pharmaceutical formulations of sofpironium bromide are 1.25 w / w% hydroxypropyl cellulose, 2.5 w / w% isopropyl myristate, 0.05 w / w% anhydrous citric acid, and 10 w / w% based on the total dosage. The preparation according to any one of claims 1 to 14, wherein the hexylene glycol of the above and absolute ethanol are composed as a residue.
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| US20150259283A1 (en) | 2014-03-13 | 2015-09-17 | Brickell Biotech, Inc. | Formulation for soft anticholinergic analogs |
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