JP6482243B2 - Pharmaceutical composition for prevention or treatment of sensory neuropathy in peripheral neuropathy - Google Patents

Description

  The present invention relates to a pharmaceutical composition useful for the prevention or treatment of sensory neuropathy in peripheral neuropathy.

  More specifically, the present invention relates to silodosin (chemical name: (−)-1- (3-hydroxypropyl) -5-[(2R) -2-({2- [2- (2,2,2- Sensory sensation in peripheral neuropathy containing trifluoroethoxy) phenoxy] ethyl} amino) propyl] -2,3-dihydro-1H-indole-7-carboxamide), or a pharmacologically acceptable salt thereof as an active ingredient The present invention relates to a pharmaceutical composition useful for prevention or treatment of neuropathy.

  Peripheral neuropathy is one of the most frequent of all nervous system diseases. Causes can be genetic or acquired (due to addictive, metabolic, traumatic, infectious, or inflammatory symptoms). Peripheral neuropathy is thought to occur as a result of local and systemic effects, these factors alone or in combination.

  Peripheral neuropathy can be classified into motor neuropathy, sensory neuropathy, and autonomic neuropathy, and clinical symptoms can be classified into positive symptoms and negative symptoms.

Sensory neuropathy includes clinical symptoms such as abnormal sensation, hypersensitivity, chronic pain (peripheral neuropathic pain), and sensory decline (sensory bluntness). The abnormal sensation includes a spontaneous abnormal sensation (no discomfort) and an illusion of feeling an unpleasant sensation different from normal by stimulation. In particular, when tactile stimulation causes unpleasant pain, it is called allodynia. On the other hand, sensory decline is less sensitive to pain, touch or temperature.
Motor neuropathy includes clinical symptoms such as muscle spasm, fiber bundle spasm, muscle weakness, and muscle atrophy.
Autonomic neuropathy includes cardiovascular abnormalities (such as dizziness), digestive system abnormalities (such as constipation), bladder disorders (urine storage disorders, dysuria), sweating disorders (such as reduced sweating), and yin (erection disorders) (See Non-Patent Document 1).

Among peripheral neuropathies, diabetic neuropathy develops from the earliest stages of diabetes, and is the most common chronic complication of diabetes in almost half of patients, especially in advanced cases with decreased insulin secretion. It is symptom. At the initial stage, most patients are unaware and asymptomatic, and often progress to treatment-resistant end-stage diabetic neuropathy without appropriate evaluation and diagnosis.
In end-stage diabetic neuropathy, sensory neuropathy leads to sensory neuropathy, lower limb ulcer formation and amputation, motor neuropathy, tipping and fracture, and autonomic neuropathy. Increases the frequency of sudden death.

Examples of drugs for treating peripheral neuropathy include mecobalamin, which is a vitamin B12 preparation, but its therapeutic effect is not sufficient.
Among peripheral neuropathies, diabetic neuropathies have low treatment satisfaction and little progress has been made in the development of new drugs. Drugs for the treatment of diabetic neuropathy include epalrestat, an aldose reductase inhibitor, mexiletine hydrochloride, a sodium channel inhibitor, pregabalin, a neurotransmitter release inhibitor, and a serotonin / noradrenaline reuptake inhibitor. There is a certain duloxetine hydrochloride etc. (refer nonpatent literature 2).
However, the therapeutic effect of the above drugs is not always sufficient. Moreover, the main effect | action is an effect | action with respect to nervousness, a pain, and a numbness, The effect | action with respect to the sensory fall accompanying diabetic neuropathy is not known.
Since sensory decline associated with diabetic neuropathy triggers gangrene related to life prognosis, drugs that have a therapeutic effect on sensory decline associated with diabetic neuropathy may increase the patient's QOL.

  Silodosin is an α1 receptor blocker and is known to be useful as a therapeutic agent for dysuria associated with prostatic hypertrophy, overactive bladder associated with neuropathy and ureteral stone disease (Patent Documents 1 to 5). ). However, silodosin is not known to be useful for the treatment of sensory neuropathy in peripheral neuropathy.

Japanese Patent Laid-Open No. 06-220015 International Publication No. 2005/085195 International Publication No. 2006/038611 International Publication No. 2006/038619 International Publication No. 2007/060974

Special editing: Akio Minami (Hokkaido University), “Latest Orthopedic Surgery System Vol. 22, Peripheral Neurological Disorders, Muscle Disorders, Circulation Disorders”, Nakayama Shoten, December 10, 2007, p. 22-26 Yokota Chitsuko, 8 others, “Disease and Drug Perfect BOOK 2012”, Nanzando, March 2012, Special Issue (Vol. 63, No. 4), p. 619-624

  An object of the present invention is to provide a pharmaceutical composition useful for the prevention or treatment of sensory neuropathy in peripheral neuropathy, particularly for prevention or treatment of sensory decline associated with sensory neuropathy in peripheral neuropathy.

  The present invention relates to a pharmaceutical composition for preventing or treating sensory neuropathy in peripheral neuropathy, comprising silodosin or a pharmacologically acceptable salt thereof as an active ingredient.

That is, the present invention relates to the following [1] to [4] and the like.
[1] A pharmaceutical composition for preventing or treating sensory neuropathy in peripheral neuropathy, comprising silodosin or a pharmacologically acceptable salt thereof as an active ingredient.
[2] The pharmaceutical composition according to the above [1], wherein the sensory neuropathy in the peripheral neuropathy is sensory reduction associated with the sensory neuropathy in the peripheral neuropathy.
[3] The pharmaceutical composition according to the above [1] or [2], wherein the sensory neuropathy in the peripheral neuropathy is diabetic neuropathy.
[4] A pharmaceutical composition for preventing or treating sensory decline associated with diabetic neuropathy, comprising silodosin or a pharmacologically acceptable salt thereof as an active ingredient.

  In another embodiment, the present invention relates to a pharmaceutical composition for preventing or treating allodynia associated with sensory neuropathy in peripheral neuropathy, comprising silodosin or a pharmacologically acceptable salt thereof as an active ingredient. It is.

  The pharmaceutical composition of the present invention has an effect of improving hypersensitivity associated with diabetic neuropathy and an effect of improving sensory decline associated with diabetic neuropathy, and is useful for the prevention or treatment of sensory neuropathy in peripheral neuropathy. .

2 shows the time course of nociceptive threshold in STZ-induced diabetic rats (average of 17-20 cases + standard error). In the figure, the horizontal axis represents time (Weeks), and the vertical axis represents nociceptive threshold (g). In the figure, white circles indicate values in the normal group (Normal), and black circles indicate values in the control group (Control). The effect of silodosin (mean value of 19-20 cases + standard error) on the nociceptive threshold of STZ-induced diabetic rats at 2 weeks after drug treatment is shown. In the figure, the bar graphs show values of the normal group, the control group (Control), the silodosin 0.3 mg / kg / day administration group, and the silodosin 1.0 mg / kg / day administration group from the left, respectively. The vertical axis represents the nociceptive threshold (g). ## indicates P <0.01 with respect to the control group. ** indicates P <0.01 with respect to the control group. The effect of silodosin (average of 14-18 cases + standard error) on the nociceptive threshold of STZ-induced diabetic rats at 10 weeks after drug treatment is shown. In the figure, the bar graphs show values of the normal group, the control group (Control), the silodosin 0.3 mg / kg / day administration group, and the silodosin 1.0 mg / kg / day administration group from the left, respectively. The vertical axis represents the nociceptive threshold (g). ## indicates P <0.01 with respect to the control group. * And ** indicate P <0.05 and P <0.01, respectively, with respect to the control group.

  Silodosin can also be produced by a known method, for example, a method described in JP-A-06-220015 or a method analogous thereto.

  Examples of pharmacologically acceptable salts of silodosin include hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, succinic acid, fumaric acid, citric acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. 2,4-dimethylbenzenesulfonic acid, 2,4,6-trimethylbenzenesulfonic acid, (+)-camphorsulfonic acid, (-)-camphorsulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 1 -Acid addition products with butanesulfonic acid, glutamic acid, aspartic acid and the like can be mentioned.

The active ingredient of the present invention includes solvates with pharmacologically acceptable solvents (for example, water, ethanol, etc.).
In addition, the active ingredient of the present invention can be converted into a prodrug and used. Prodrugs are described, for example, in “Development of Pharmaceuticals” (Yodogawa Shoten, 1990), Volume 7, p. It can also be produced by introducing the group described in 163-198.

  Examples of the dosage form of the pharmaceutical composition of the present invention include oral administration such as tablets, capsules, granules, powders, fine granules, and dry syrups, or injections, patches, suppositories, inhalants, and nasal drops. Any form of parenteral administration by an agent or the like may be used.

  The pharmaceutical composition of the present invention is prepared using silodosin or a pharmacologically acceptable salt thereof and at least one pharmaceutical additive. These pharmaceutical compositions are prepared according to pharmacologically known techniques depending on the dosage form, using appropriate excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, It can also be prepared by appropriately mixing, diluting or dissolving with pharmaceutical additives such as wetting agents, emulsifiers, dispersants, stabilizers, solubilizers and the like.

The dosage of silodosin may be determined as appropriate according to the patient's weight, age, sex, degree of disease, and the like. For example, the dose for an adult is 1 to 50 mg / day, preferably 1 to 16 mg / day, more preferably 4 to 8 mg / day for oral administration, and 0.5 to 5 mg / day for parenteral administration. In the range of days, preferably 1-2 mg / day. The daily dose can be administered once, or divided into two or more (preferably 2 or 3 times).

  In the present invention, peripheral neuropathy includes diseases represented by the terms motor neuropathy, sensory neuropathy, and autonomic neuropathy. However, the clinical symptoms of sensory neuropathy in the peripheral neuropathy of the present invention do not include bladder disorders (urine accumulation disorder and dysuria) associated with peripheral neuropathy.

  The pharmaceutical composition of the present invention is useful for the prevention or treatment of metabolic neuropathy such as diabetic neuropathy.

Moreover, as one aspect, the pharmaceutical composition of the present invention comprises Guillain-Barre syndrome, Charcoma Tooth disease, hereditary sensory neuropathy, acute inflammatory demyelinating sensory neuropathy, chronic sensory ganglionitis, chronic inflammatory Peripheral neuropathy such as demyelinating polyneuropathy, vasculitis / collagenous peripheral neuropathy, peripheral neuropathy associated with carpal tunnel syndrome, peripheral neuropathy associated with obstructive arteriosclerosis, and peripheral neuropathy associated with Buerger's disease It is useful for the prevention or treatment of sensory neuropathy in neuropathy.

  In the present invention, clinical symptoms of sensory neuropathy in peripheral neuropathy include abnormal sensation, hypersensitivity, chronic pain, sensory decline and the like. However, the clinical symptoms of sensory neuropathy in the peripheral neuropathy of the present invention do not include muscle weakness, muscle atrophy, orthostatic hypotension, constipation, reduced sweating and yin wilt.

  Peripheral neuropathy can also be examined and diagnosed by interrogation and sensation, proprioception, exercise intensity, and deep tendon reflex evaluation. As an auxiliary diagnosis, electrophysiological tests, blood tests, cerebrospinal fluid tests, genetic diagnosis, and biopsy can also be performed. Examination and diagnosis of diabetic neuropathy can be performed, for example, as a physical examination by a quantitative sensory test such as vibration sense, pressure sensation, thermal sensation, and sharpness of the tip of the lower limb, and an Achilles tendon reflex. In addition, the examination and diagnosis of diabetic neuropathy are, for example, literature (Chiyoko Yokota, 8 others, “Disease and Drug Perfect BOOK 2012”, Minamiyamado, March 2012, Special Issue (Vol. 63, No. 4), p.620-622).

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to the contents thereof.

Measurement of nociceptive threshold in diabetic neuropathy model rats (1) Measurement of nociceptive threshold
SD rats (male, 7 weeks old, 20 cases each group, Nippon Charles River Co., Ltd.), 0.1N (
Streptozotocin (STZ) dissolved in citrate buffer (pH 4.5)
The solution was intravenously administered from the tail vein (50 mg / kg, 1 mL / kg) to induce diabetes. The normal group (Normal) was intravenously administered with 0.1 N citrate buffer (1 mL / kg). One week after administration of STZ or 0.1 N citrate buffer, silodosin dihydrobromide solution (0.3 or 1.0 mg / kg / day as silodosin) dissolved in Hartmann solution under ether anesthesia and its solvent (Hartmann solution) An implantable mini-osmotic pump (2ML4, Alzet (registered trademark)) encapsulated in the skin was implanted subcutaneously. The mini-osmotic pump was replaced with a new pump after 4 weeks. The nociceptive threshold was measured every 2 weeks after STZ treatment (Randall-Selitto method).
(2) Results In the control group (solvent-administered group), a decrease in nociceptive threshold (hypersensitivity) was confirmed at the initial stage of the disease at 2 weeks, and an increase in nociceptive threshold (decreased perception) at the end of the pathology after 8 weeks. Was observed (Figure 1).
In the early stage of the disease at 2 weeks, silodosin significantly suppressed the decrease in nociceptive threshold, indicating that silodosin has an effect of improving hypersensitivity associated with diabetic neuropathy (Fig. 2).
. In addition, silodosin significantly suppressed the increase of the nociceptive threshold at the end of the pathological condition at 10 weeks, indicating that silodosin has an effect of improving sensory decline associated with diabetic neuropathy (FIG. 3).

From the results of Example 1, it was suggested that silodosin is useful as a drug that suppresses not only hypersensitivity in the early stage of diabetic neuropathy but also sensory decline in the end stage of diabetic neuropathy. Therefore, it is suggested that silodosin is useful as a preventive or therapeutic agent for sensory neuropathy in peripheral neuropathy.

  The pharmaceutical composition of the present invention is extremely useful as a pharmaceutical composition for preventing or treating sensory neuropathy in peripheral neuropathy.

Claims (2)

A pharmaceutical composition for preventing or treating diabetic neuropathy , comprising silodosin or a pharmacologically acceptable salt thereof as an active ingredient. A pharmaceutical composition for preventing or treating hypoxia associated with diabetic neuropathy, comprising silodosin or a pharmacologically acceptable salt thereof as an active ingredient.

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